substrate specificities among the protein kinases, there are also common structural features. These conserved structural motifs provide clear indica- tions as to ...
PROTEIN KINASES
6
The eukaryotic .
(catalytic)
protein
superfamily:
kinase
S
.
domam structure
idnase .
and classification
1
STEVEN K.. HANRS* AND TONY HUNTER2 *Department of Cell Biology, Vanderbilt University School of Medicine, Nashville, Tennessee Molecular Biology and Virology Laboratory, The Salk Institute, San Diego, California 92186, The eukaryotic protein kinases comprise one of the largest superfamilies of homologous proteins and genes. Within this family, there are now hundreds of different members whose sequences are known. Although there is a rich diversity of structures, regulation modes, and substrate specificities among the protein kinases, there are also common structural features. These conserved structural motifs provide clear indications as to how these enzymes manage to transfer the phosphate of a purine nucleotide triphosphate to the hydroxyl groups of their protein substrates. The authors of this review have carried out a monumental task of analyzing and collating the amino acid sequences of all reported protein kinases and defining the conserved structural features that characterize the portion of these proteins that is responsible for their catalytic activity. Comparison of the sequences in the catalytic fragment of the protein kinases has been used to arrange these enzymes in evolutionary trees that group subfamilies of closely related enzymes. It is comforting that the structural relationships that emerge from these trees result in groupings that also reflect related functions. The work presented in this review seems to be an excellent example of the type of analysis that will become indispensable in the coming years, as more and more sequence information become available to biologists as a result of the genome projects. The eukaryotic protein kinases make up a large superfamily of homologous proteins. They are related by virtue of their kinase domains (also known as catalytic domains), which consist of “‘250-300 amino acid residues. The kinase domains that define this group of enzymes contain 12 conserved subdomains that fold into a common catalytic core structure, as revealed by the 3-dimensional structures of several protein-serine kinases. There are two main subdivisions within the superfamily: the protein-serine/threonine kinases and the protein-tyrosine kinases. A classification scheme can be founded on a kinase domain phylogeny, which reveals families of enzymes that have related substrate specificities and modes of regulation.-Hanks, S. K., Hunter, T. The eukaryotic protein kinase superfamily: kinase (catalytic) domain structure and classification. FASEB J. 9, 576-596 (1995) ABSTRACT
Key Words:
protein-tyrosine
nose. protein phosphorylation THE EUKARYOTIC
k inase protein-serine AMP-dependent
PROTEIN
KINASE
hi-
protein kinose SUPERFAMILY
One of the largest known protein superfamilies is made up of protein kinases identified largely from eukaryotic
576
37232, USA; and USA
sources. (The term superfamily will be used here to distinguish this broad collection of enzymes from smaller, more closely related subsets that have been commonly referred to as families). These enzymes use the y-phosphate of ATP (or GTP) to generate phosphate monoesters using protein alcohol groups (on Ser and Thr) and/or protein phenolic groups (on Tyr) as phosphate acceptors. The protein kinases are related by virtue of their homologous kinase domains (also known as catalytic domains), which consist of 250-300 amino acid residues (reviewed in refs 1-3; and see below). During the past 15 years, previously unrecognized members of the eukaryotic protein kinase superfamily have been uncovered at an exponentially increasing rate and currently appear in the literature almost weekly. This pace of discovery can be attributed to the past development of molecular cloning and sequencing technologies and, more recently, to the advent of the polymerase chain reaction (PCR),3 which facilitated the use of homology-based cloning strategies. Consequently, about 200 different superfamily members (products of distinct paralogous genes) had been recognized from mammalian sources alone! The prediction made several years ago (4) that the mammalian genome contains about 1000 protein kinase genes (roughly 1% of all genes) would still appear to be within reason, and may even be an underestimate (5). In addition to mammals and other vertebrates, cukaryotic protein kinase superfamily members have been identified and characterized from a wide range of other animal phyla as well as from plants, fungi, and protozoans. Hence, the protein kinase progenitor gene can be traced back to a time before the evolutionary separation of the major eukaryotic-like
eukaryotic protein
kingdoms. The identification kinase genes in prokaryotes
of (6, 7)
raises gene
the possibility that the protein kinase progenitor might have arisen before the divergence of prokaryotes and eukaryotes (see below). Studies of the budding and fission yeasts, Saccharomyces cerevi.ciae and Schizosaccharomyces pombe, have been particularly fruitful in the recognition of new protein kinases. In these geneti-
‘This article is based on an introductory chapter in the Protein Kinase Facisbook, edited by D. G. Hardie and S. K. Hanks, publish-
ed in 1995 by Academic Press, London. 2To whom correspondence and reprint requests should be addressed, at: Molecular Biology and Virology Laboratory, The Salk Institute, 10010 N. Torrey Pines Rd., La Jolla, CA 92037, USA. 5Abbreviations: PCR, polymerase chain reaction; PKA-Ca, type a cAMP-dependent protein kinase catalytic subunit; Cdk2, cyclin-dependent kinase 2; Erk2, p42 MAP kinase; APE,
0892-6638/9510009-0576/$O1.50. ©
FASEB
SERIAL cally tractable organisms, the powerful approach of mutant isolation and cloning by complementation has netted dozens of protein kinase genes required for numerous aspects of cell function (8). In many cases, vertebrate counterparts have now been found for these genes, leading to a growing awareness that protein phosphorylation pathways that regulate basic aspects of cell physiology have been maintained throughout the course of eukaryotic evolution. Even though the overwhelming majority of protein kinases identified from eukaryotic sources belong to this superfamily, a small but growing number of such enzymes do not qualify as superfamily members. Most of these are related to the prokaryotic protein-histidine kinase family (see below), which forms the sensor components of twocomponent signal transduction systems (9). Included in this category are a putative ethylene receptor encoded by the flowering plant ETR1 gene (10), the product of the budding yeast SLN1 gene (11, 12) thought to be involved in relaying nutrient information to elements controlling cell growth and division, the mitochondrial branched-chain a-ketoacid dehydrogenase kinase (13), and the mitochondrial pyruvate dehydrogenase kinase
(14). In prokaryotes, protein-histidine kinases phosphorylate aspartates in their target proteins, but except for the two dehydrogenase kinases that phosphorylate serine, the acceptor specificities of most of the eukaryotic protein kinases of this type are not known. In addition to these protein kinases, the Bcr protein encoded by the breakpoint cluster region gene involved in the Philadelphia chromosome translocation (15) and the A6 kinase isolated by expression cloning using an anti-phosphotyrosine antibody (16) have kinase domains unrelated to any known eukaryotic or prokaryotic kinase. In addition, true protein-histidine kinases are known in eukaryotes. One such enzyme has been extensively characterized from budding yeast but not yet molecularly cloned (17), and so it is not clear whether this enzyme will belong to the protein kinase superfamily or use a novel structural principle for phosphotransfer. What about the prokaryotes? It has been known for years that protein phosphorylation events play key regulatory roles in numerous bacterial cell processes including chemota,cis, bacteriophage infection, nutrient uptake, and gene transcription (reviewed in refs 18, 19). The bacterial protein kinases have been divided into three general classes (20): 1) protein-histidine kinases such as those functioning in two-component sensory regulatory systems (strictly speaking, these are protein-aspartyl kinases, because autophosphorylation on His is an intermediary step in phosphotransfer to an aspartate in the response-regulator protein) (9); 2) phosphotransferases such as those of the phosphoenol pyruvate-dependent phosphotransferase system involved in sugar uptake (21); and 3) protein-serine kinases such as isocitrate dehydrogenase kinase/phosphatase (22). Amino acid sequences have been determined for members of each class, and all are unrelated to the eukaryotic protein kinase superfamily.
Recently,
true homologs of the eukaryotic been identified from two species of bacteria, Yersinia pseudotuberculosis (7) and Myxococcus xanthus (6, 23). Are these special cases, or the first examples of many such genes in prokaryotes? The eukaryotic-like protein kinase YpkA from the pathogenic enterobacteria Y. pseudotuberculosis is encoded by a plasmid essential for protein
however,
kinases
have
EUKARYOTIC PROTEIN KINASE SUPERFAMILY
REVIEW
the virulence of this infectious organism. In addition to YpkA, at least two other proteins encoded by genes residing on the virulence plasmid exhibit high similarity to eukaryotic proteins. Thus, it seems likely that the virulence plasmid genes were transduced from a eukaryotic host by horizontal transfer. The myxobacterium M xanthus presents a different and perhaps more intriguing picture. Application of the PCR homology-based cloning strategy revealed that at least eight genes encoding members of the eukaryotic protein kinase superfamily are present in the genome of this species (23). The myxobacteria are unusual prokaryotes in that they undergo a complex developmental cycle upon nutrient depletion, much like that of the eukaryotic slime mold Dictyostelium. Given that protein kinases are commonly involved in regulating growth and differentiation of eukaryotic cells, it is attractive to speculate that the eukaryotic-like protein kinases in M. xanthus are specifically involved in regulating their developmental cycle. Indeed, one of these kinases, Pkn 1, was shown to be required for proper fruiting body formation. The same could be true for the eukaryotic-like protein kinase PknA from Anabena (24). In keeping with this idea, neither the PCR approach applied to Escherichia coli (23) nor extensive sequencing of the E. coli genome (now 30% complete) has yielded eukaryotic-like protein kinases. Hence, genes encoding members of the eukaryotic protein kinase superfamily may be present only in bacteria that can undergo a developmental cycle. However, unpublished reports of eukaryotic-like protein kinases in Streptomyces coelicolor, and in three species of Methanococcus, suggest that such genes are more widely expressed among prokaryotes, and potentially these genes represent the ancestors for the entire eukaryotic protein kinase superfamily.
THE
HOMOLOGOUS
KINASE
DOMAINS
The kinase domains of eukaryotic protein kinases impart the catalytic activity. Three separate roles can be ascribed to the kinase domains: 1) binding and orientation of the ATP (or GTP) phosphate donor as a complex with divalent cation (usually Mg2 or Mn2’); 2) binding and orientation of the protein (or peptide) substrate; and 3) transfer of the y-phosphate from A1’P (or GTP) to the acceptor hydroxyl residue (Ser, Thr, or Tyr) of the protein substrate. Conserved
features
of primary
structure
The total number of distinct kinase domain amino acid sequences available is now approaching 400 (Table 1). Included in this total are the vertebrate enzymes encoded by distinct paralogous genes, their presumed functional homologs from invertebrates and simpler organisms (encoded by orthologous genes), and those identified from lower organisms and plants for which vertebrate equivalents have not been found. Conserved features of kinase domain primary structure have previously been identified through an inspection of multiple amino acid sequence alignments (1-3) The large number of sequences now available precludes showing an alignment containing all known kinase domains. Thus, in Fig. 1 only 60 different kinase domain sequences are aligned. These are drawn, however, from the widest possible sampling of the superfamily and thus provide a good representation of the .
577
SERIAL Table
REVIEW
1. Eukaiyotic protein kinase superfamily class[ication.
A-C-G Group AGC-I. Cyclic nucleotide-regulated protein kinase family A. Cyclic AMP-dependent protein kinase (PEA) subfamily vertebrate: 1. PEA-Ca: PEA catalytic PEA catalytic 2. PKA-C: 3. PEA-Or PEA catalytic Drosophila melanogaster PEA catalytic 1. DmPEA-CO: PEA catalytic 2. DmPEA-C1: 3. DmPEA-C2: PEA catalytic Caenorhabditis elegans: 1. CePKA: PEA catalytic Saccharomyces cerevisiae:
subunit, CO form subunit, Cl form subunit, C2 form subunit homolog
PEA catalytic subunit homolog,
I. ScPKA-TpkI: Schizosaccharomyces pombe: 1. SpPKA1: Dictyostelium discoideum: 1. DdPEA: Aplysia calfornico: 1. ApIC:
2. Sak: B. Cyclic GMP-dependent
subunit, alpha-form subunit, beta-form subunit, gamma-form
type I
PEA catalytic subunit homolog PEA catalytic subunit
protein
PEA catalytic subunit “Spermatozoon-associated kinase (PKG) subfamily
homolog kinase”
vertebrate:
1. PKG-I:
PKG, type I PKG, type II
2. PKG-II: Drosophila melanogaster: *
1. DmPKC-G1: 2. DmPKG-G2:
PKG homolog, PKG homolog,
type I type 2
C. Others Dictyostelium discoideum: 1. DdPKI: AGC-IL
PEA homolog protein kinase C (PKC) family protein kinase C (cPKC) subfamily
Diacyiglycerol-activated/phospholipid-dependent
A. “Conventional”
(Ca” -dependent)
vertebrate: 1. cPKCa: 2. cPKCl: 3. cPKC Drosophila melanogaster: 1. DmPKC-53Ebr:
Protein Kinase C, alpha-form Protein Kinase C, beta-form Protein Kinase C, gamma-form PKC homolog PKC homolog
2. DmPKC-53Eey:
expressed
expressed
in brain, locus 53E in eye, locus 53E
Aplysia cal[ornica: 1. ApI-I:
B. “Novel” (Ca ‘-independent)
Protein
Kinase
PKC homolog, type I C (nPKC) subfamily
vertebrate:
1. nPKC6: 2. nPKCc: 3. nPKCr: 4. nPKCO: Drosophila melanogaster: 1. DmPKC-98F: Aplysia cal!ft’rnica: 1. ApI-H: Caenorhabditis elegans: 1. CePKC: * 2. CePKCIB: Dictyostelium discoideum:
I. DdMHCK:
*
2. ScPEA2:
Schizosaccharomyces 1. Pckl:
C, C, C, C,
PKC homolog,
locus 98F
PKC homolog,
type II
PKC homolog, PKC homolog
delta-form epsilon-form eta-form theta-form
product of tpa-1 gene expressed
in neurons
and interneurons
PKC homolog
Saccharomyces cerevisiae: 1. ScPEAI: *
Protein Kinase Protein Kinase Protein Kinase Protein Kinase
PKC homolog, PKC homolog,
of PKCJ gene product of PKC2 gene product
pombe:
“Pombe C-kinase”, type 1 2. Pck2: “Pombe C-kinase”, type 2 C. “Atypical” Protein Kinase C (aPKC) subfamily vertebrate: *
1. aPKC1: 2.
*
4.
Protein Protein Protein
Kinase C, zeta-form Kinase C, iota-form Kinase C, mu-form
‘More information about the individual protein kinases listed (including sequence references) can be obtained by contacting the authors or by consulting The Protein Kinase Factsbook (42). Protein kinases marked with asterisks (*) were not included in the phylogenetic analysis due to their recent discovery. In many instances new protein kinases were cloned by more than one group; in these cases the most commonly accepted name is used for the entry and alternative names are listed in parentheses after the entry. Protein kinase homologs from DNA viruses are not included in this classification.
578
Vol.
9
May
1995
The
FASEB Journal
HANKS
AND
HUNTER
SERIAL Table
REVIEW
1. (continued).
D. Others vertebrate:
1.PKN:
*
Protein
kinase with PKC-related
AGC-III. Related to PEA and PKC (RAC) family vertebrate: RAC, alpha-form; I. RAC-ct: RAC, beta-form 2. RAC-: Drosophila: I. DmRAC: RAC homolog caenorhabditis elegans: * I. CeRAC: RAC homolog
ACC-IV. Family of kinasese that phosphorylate vertebrate: I. ARK1: 2. ARK2: 3.RhK: *
4.IT11:
cellular
C protein-coupled
I. DmGPRK1: 2. DmGPRK2: AGC-V. Family of budding yeast AGC-related Saccharomyces cerevisiae:
homolog
of v-Akt oncoprotein
receptors
-adrenergic receptor (1-adrenergic receptor Rhodopsin kinase C-protein-coupled C-protein-coupled C-protein-coupled
5.GRK5: * 6. GRK6: Drosophila nwlanogaster. *
catalytic domain
kinase, type 1 kinase, type 2 kinase homolog kinase, type 5 kinase, type 6
receptor receptor receptor
C-protein-coupled
receptor
kinase,
Drosophila
C-protein-coupled
receptor
kinase, type 2
kinases
I. Sch9:
Suppressor
2. Ykr2: S. Ypkl:’
AGC-related AGC-related
of defects in cAMP effector
pathway
kinase kinase
AGC-VI. Family of kinases that phosphorylate ribosomal S6 protein vertebrate: 1. S6K: 70 kDa S6 kinase with single catalytic domain 2. RSK1(Nt): 90 kDA S6 kinase, type 1 3. RSK2(Nt): 90 kDA S6 kinase, type 2 [Note: The RSK enzymes have two distinct catalytic domains. The Nt-domain Ct-domain
is most closely
AGC-VII. Budding yeast Dbf2/2O Family Saccharomyces cerevisiae: 1. Dbf2: 2. Dbf2O:
type 1
Drosophila
related
to phosphorylase
is closely
related
to S6K, whereas
the
kinase]
Product of gene periodically expressed in cell cycle Close relative of DBF2 not under cell cycle control
AC-VIII. Flowering plant “PVPKl Family” of protein kinase homologs Phylum Angiospmnophyta (Kingdom Plantae): I. PvKI: Bean protein kinase homolog 2. 3. 4. 5. 6. 7.
OsGl 1A: ZmPPK: AtPK5: AtPK7: AtPK64: PsPKS:
Other AGC-related
Rice protein kinase homolog Maize protein kinase homolog Arabidopsis protein kinase homolog Arabidopsis protein kinase homolog Arabidopsis protein kinase homolog Pea protein kinase homolog
kinases
vertebrate: “Myotonic Dystrophy Protein Kinase”
I. DMPK: 2. Sgk:
“Serum and glucocortocoid regulated kinase” Spermatid “Microtubule-associated serine/threonine
3 Mast2O5: Neurospora crassa: *
1. NcCot-1: Dietyostelium discoideum:
Product
of gene required
1. Ddk2:
Product
of developmentally-regulated
Saccharomyces cerevisiae: 1. ScSpkl:
Dual-specificity
for normal
colonial
kinase”
growth
gene
kinase
Phylum Angiospermophyta (Kingdom Plantae): *
I. Atpkl:
CaMK Group CaMK-I. Family of kinases A. Subfamily including
Arabidopsis
protein
kinase
regulated by Ca’7Calmodulin, and close relatives “Multifunctional” Ca’/Calmodulin Kinases (CaMKs)
vertebrate: I. CaMK1: 2. CaME2a: 3. CaMK2fr 4. CaMK2r 5. CaMK2&: * 6. EF2K: 7. CaMK4:
EUKARYOTIC PROTEIN KINASE SUPERFAMILY
CaMK, type I CaMK, type II, alpha subunit CaMK, type II, beta subunit CaMK, type II, gamma subunit CaMK, type II, delta subunit Elongation Factor-2 Kinase or CaMK type III CaMK, type IV
579
SERIAL Table
REVIEW
1. (continued). Drosophila melanogaster: 1. DmCaMK2: Saccharomyces cerevisiae: 1. ScCaMK2-1: 2.ScCaMK2-2: Aspergilins nidulans:
CaMK-II homolog CaMK-II homolog, CaMK-II homolog,
I. AnCaMK2: B. Subfamily including vertebrate: I. PhK-yM: 2. PhK-/T: 3.
of CMKI gene of CMK2 gene
CaMK-II homolog phosphorylase
kinases
RSK1(Ct):
4. RSK2(Ct): C. Subfamily including vertebrate: 1.skMLCK: 2. smMLCK: 3. Titin:
product product
myosin
light chain
Skeletal muscle phosphorylase kinase Male germ cell phosphorylase kinase 90 kDa S6 kinase, type 1; C-terminal 90 kDa S6 kinase, type 2; C-terminal kinases Skeletal muscle MLCK (rabbit) Smooth muscle MLCK (rabbit) Huge protein implicated in skeletal
catalytic subunit catalytic subunit catalytic domain catalytic domain
muscle
development
Caenorhabditis elegans: ‘Twitchin” protein involved in muscle contraction or development 1. Twn: Dictyostelium discoideum: 1. DdMLCK: Slime mold myosin light chain kinase D. Subfamily of plant kinases with intrinsic calmodulin-like domain Phylum Angiospermophyta (Kingdom Plantae): 1.CDPK: Soybean Ca2-regulated kinase with intrinsic CaM-like domain * *
2. AtAKI: 3 OsSpk: 4. DcPk43l:
Arabidopsis CDPK homolog Rice CDPK homolog Carrot CDPK homolog
E. Subfamily of plant kinaseswith highly acidicdomain Phylum Angiospermophyta (Kingdom Plantae): * 1.ASK1: Arabidopsis protein kinase homolog *
2. ASK2:
Arabidopsis
F. Other CaMK-related kinases vertebrate: 1.PskHl: * 2. Saccharomyces cerevisiae: 1. Mre4: * 2.Dunl: * 3.Rckl: *
Putative protein-serine “MAP Kinase-Activated
4. Rck2:
2: p78: Saccharomyces cerevisiae: 1.Snfl: 2. KinI: 3. Kin2: 4. Yc124: * 5.Ycl453: Schizosaccharomyces pombe: 1.SpKinl: 2. NimI: Phylum Angiospermophyta (Kingdom
*
essential
for release
from glucose
repression
Product Inducer
on chromosome on chromosome
of gene important of mitosis
for growth
III XI polarity
Planlae): Rye putativeprotein kinase thatcomplements yeastsnfl polarity Arabidopsis putativeprotein kinase relatedto SNFI Barley protein related to SNFI Wheat kinase induced by abscisic acid Wheat kinase homolog regulated by light and nutrients Tobacco Snfl homolog, activates SUC2 gene expression
(malarial parasite):
C-M-G-C Group CMGC-I. Family of cyclin-dependent vertebrate: 1. Cdc2: 2. Cdk2: 3. Cdk3: 4. Cdk4: 5. Cdk5:
May 1995
pancreas
Close relative of KIN1 Protein kinase homolog Protein kinase homolog
Ca’-regulated
1. PfCPK: 2. PfPK2:
Vol. 9
“AMP-Activated Protein Kinase” Protein lost in carcinomas of human
Kinases
Plasmodiumfalciparum
580
kinase, type 1” kinase, type 2”
Protein kinase with N-terminal catalytic domain
2. PSnfl-AKIN1O: 3. PSnfl-BKINI2: 4. PKABA1: 5 WPK4: 6. NPK5:
Other CaMK Group
Kinase 2”
‘Radiation sensitivity complementing “Radiation sensitivity complementing
Kinase
1. PSnfl-RKIN 1:
*
kinase Protein
Protein required for meiotic recombination Protein required for DNA damage-inducible gene expression
CaMK-lI. Snfl/AMPK family vertebrate: * 1:AMPK:
*
with highly acidic idomain protein kinase homolog with highly acidic domain
Putative kinases
(CDKs)
protein
and other
Inducer Type 2 Type 3 Type 4 Type 5
kinase with intrinsic CaM-like domain kinase close relatives
of mitosis; functional homolog cyclin-dependent kinase cyclin-dependentkinase cyclin-dependent kinase cyclin-dependent kinase
The FASEBJournal
of yeast cdc2+/CDC28
kinases
(Cdkl)
HANKS
AND
HUNTER
SERIAL REVIEW Table
1. (continued).
6. Cdk6: 7. PCTAIRE1: 8. PCTAIRE2: 9. PCTAIRES:
Type 6 cyclin.dependent
kinase
Cdc2-related protein Cdc2-related protein Cdc2-related protein “Cdk-activating kinase”; Negative
10. Mo 15: Drosophila melanogaster: 1. DmCdc2: 2. DmCdc2c: Dictyostelium discoideum: I. DdCdc2: 2. DdPRK: A.spergillus nidulans: I. NIMXcdc2: Plasmodiumfalciparum: 1. PfPK5: Entamoeba histolytica: 1. EhC2R: Crithidiafascicutata: I. CfCdc2R:
kinases
Functional
kinases
homolog
of yeast cdc2+/CDC28
(CAK)
PCTAIRE Kinase”
Cdc2-related
gene product
Cdc2-related
protein
Cdc2-related
protein
Cdc2-related
protein
“Cdc2-Related
Saceharomyces cerevisiae: 1. Cdc28: 2. Pho85: 3. Kin28: Schizosaccharomyces pombe: I. SpCdc2: Histoplasma capsulatum: * 1. HcCdc2: Phylum Angiosperntophyta (Kingdom I. Pcdc2: * 2. MsCdc2B: 3. OsC2R: CMGC-II. Erk(MAP kinase) family vertebrate: 1. Erkl: 2. Erk2: 3. ErkS: * 4. p63MAPK: * 5 SAPK-a: * 6. SAPK-: * 7. SAPK-/Jnk1: * 8. p38:
of meiosis
Functional homolog of yeast cdc2+/CDC28 Cdc2.cognate protein; Cdk2 homolog
“Cdc2-related
L.eishmania mexicana: * I. LmCRK1:
regulator
from
human
malarial parasite
Kinase”
“Cell-division-cycle” gene product Negative regulator of the PHO system and cell cycle regulator CDC28-related protein “Cell-division-cycle”
gene product
Cdc2 homolog from dimorphic fungus Plantae): Flowering plant Cdc2 homolog othat complements yeast mutants Alfalfa Cdc2 cognate gene products that complements Cl/S transition More distantly related Cdc2 homolog from rice
“Extracellular signal-regulated kinase”, type 1 (p44 MAP kinase) “Extracellular signal-regulated kinase”, type 2 (p42 MAP kinase) Somewhat distant relative of the Erk/MAP kinases Another more distant relative of the Erk/MAP kinases “Stress-activated protein kinase, type alpha” (JNK2) “Stress-activated protein kinase, type beta” “Stress-activated protein kinase, type gamma” or “Jun N-terminal HOGI-related protein (MPK2)
Kinase”
Drosophila melanogaster: 1. DmErkA: Homolog of Erk/MAP kinases; product of rolled gene Caenorhabd it is elegans: * I. Sun: Erk/MAP kinase Saccharomyces cerrevisiae: I. Kss 1: Suppressor of sst2 mutant, overcomes growth al-rest 2. FusS: Product of gene required for growth and mating S. S1t2: Product of gene complementing lyt2 mutants (MPK1) * 4. Hogi: Product of gene required for osmoregulation Schizosaccharomyces pombe: L Spkl: Product of gene that confers drug resistance to staurosporine, a PK inhibitor Phylum Deuteromycota (Kingdom Fungi): 1. CaErkl: Protein that interferes with mating factor-induced cell cycle arrest Trypanosoma btucei (Phylum Zoomastigina, Kingdom Protoctista): * KFR1: “KSSl- and FUSS-related” gene product Phylum Angiospermophyta (Kingdom Plantae): 1. PErk: Flowering plant Erk/MAP kinase homologs (7 distinct homologs identified in Arabidopsis) CMGC-IH. Glycogen synthase kinase 3 (GSK3) family vertebrate: 1. GSKSa: Glycogen synthase kinase 3, a-form 2. GSK3: Clycogen synthase kinase 3, il-form Drosophila melanogaster: 1. Sgg: Product of shaggy/zeste-white 3 gene Saccharomyces cerevisiae: 1. Mckl: “Meiosis and centromere regulatory kinase” * 2. ScGSK3 Protein closely related to MCK1 * 3. MdsI: Dosage suppressor of mckl mutant Dictyostelium *
discoideism:
1. DdCSKS:
Phylum Angiosperniophyta * 1. ASK-a: * 2. ASK-i
EUKARYOTIC
PROTEIN
Glycogen (Kingdom
KINASE SUPERFAMILY
synthase kinase 3
Plantae): “Arabidopsis shaggy-related “Arabidopsis shaggy-related
protein protein
kinase”, kinase”,
type alpha type gamma
581
SERIAL REVIEW Table
1. (continued). vertebrate: 1. CK2a: 1. CK2a’: Drosophila melanogaster:
Casein kinase II, alpha subunit Casein kinase II, alpha-prime subunit
1. DmCK2: Caenorhabditis
Casein
Casein kinase
1. CeCK2: Theileria parva (a protozoan
1. TpCK2:
Casein kinase II a-subunit
Angiospmnophyta 1. ZmCK2:
homolog
Casein kinase II, a-subunit Casein
kinase
II, alpha
subunit
Casein kinase II, alpha-prime
1.SpCkal:
Phylum
II homolog
parasite):
Dictyostelium discoideum: 1. DdCK2: Saccharomyces cerevisiae: 1. ScCK2a: 2. ScCK2a’: Schizosaccharomyces pombe: *
kinase II homolog
elegans:
(Kingdom
subunit
Casein kinase II, a-subunit homolog (Orb5) Plantae): Flowering plant casein kinase II, a-subunit homolog
CMGC-IV. CIk family vertebrate: *
1. CIk: 2.Srpkl:
“Cdc-like kinase” Kinase that regulates intracellular Putative protein kinase Putative protein kinase
S. PskGl: 4. PskH2: Drosophila melanogaster: * 1.Doa: Saccharomyces cerevisiae:
Kinase encoded by “Darkener
1. Yakl: 2. Knsl: Schiwsaccharomyces 1. Dskl: * 2. Prp4:
Suppressor Nonessential
* *
6.
Saccharomyces cerevi.ciae: 1. Sme 1: 2. Sgvl: S. Ctkl: Phylum Angiosperinophyta * 1. Mhk:
vertebrate: 1. Src:
2. Yes: 3. Yrk: 4. Fyn:
5. Fgr: 6. Lyn:
* * *
“Male germ cell-associated kinase” “Cholinesterase-related cell division controller” Galactosyltransferase-associated kinase Cdc2-nelated protein Cdc2-related kinase Cdc2-related kinase
Kinase
(Kingdom
Group
Product of gene essential for tart of niosis Kinase required for G-protein-mediated adaptive Product of gene required for normal growth Plantae): Arabidopsis thaliana “Mak homologous kinase” (l-X: Non-membrane-spanning;
XI-XXIH:
STK-related kinase “Fyn and Yes-related
kinase” from electric Drosophila melanogaster: 1. DmSrc: Src homolog, polytene locus 64B Dugeciai (Girardia) tigrina (Phylum Platyhelminthes): * 1. DtSpk-l: “Src-like planarian Hydra vulgaris (Phylum Cnidaria): 1. Stk: Src-related protein Spongilla lacustris (Phylum Ponfera): Four distinct Src-related kinases 1. Srkl-4:
582
Vol. 9
May 1995
to pheromone
Cellular homolog of Rous sarcoma virus oncoprotein Cellular homolog of Yamaguchi 73 sarcoma virus oncoprotein Yes-related kinase Protein related to Fgr and Yes Cellular homolog of Gardner-Rasheed sarcoma virus oncoprotein
11.Rak: 12. Fyk:
PTK-II. Brk family vertebrate: * 1. Brk:
response
Membrane-spanning)
10. Frk:
8. Lck: 9. BIk:
locus
of RAS mutant protein kinase homolog
Protein related to Fgr and Yes Hematopoietic cell protein-tyrosine kinase Lymphoid T-cell protein-tyrosine kinase Lymphoid B-cell protein-tyrosine kinase Fyn-related kinase
7. Hck:
factors
Disi-suppressing protein kinase implicated in mitotic control Pre-mRNA processing gene product; lacks subdomains X-X1
Ched: PITSLRE: KKIALRE: PITALRE:
Conventional Protein-Tyrosine PTK-l. Src family
of Apricot”
of splicing
pombe:
Other CMGC Group kinases vertebrate: 1. Mak:
2. 3. 4. 5.
localization
Protein-tyrosine
kinase expressed
The FASEB Journal
in human
ray
breast tumors
HANKS
AND
HUNTER
SERIAL
REVIEW
Table 1. (continued). PTK-I1I. Tec family vertebrate: 1. Tec: 2. Emt: 3. Btk:
‘Tyrosine kinase expressed
“Bruton’s agammaglobulinaemia
4.Txk:
*
in hepatocellular
“Expressed mainly in T-cells” kinase (ltk,
carcinoma”
Tsk)
tyrosine kinase” (Emb)
Tec-related protein.tyrosine kinase
Drosophila melanogaster: 1. DmTec:
Tec homolog,
polytene
locus 28C
PTK-IV. Csk family vertebrate: 1. * 2. PTK-V. Fes(Fps) vertebrate: 1. 2. Drosophila
“C terminal Src Kinase”; negative regulator of Src “Megakaryocyte-associated Tyr-kinase” (Hyl, Lsk, Ctk, Ntk)
Csk:
MarK: family Fes/Fps: Fer: melanogaster:
Cellular homolog “Fes/Fps-related”
1. DmFer:
Fer-related
PTK-VI. AbI family vertebrate: 1. AbI: 2. Arg Drosophila melanogaster:
Cellular
viruses
protein
homolog
of Abelson
murine
leukemia
virus
“AbI-related gene” product
1. DmAbl: Caenorhabditis
of feline and avian sarcoma kinase
AbI-related
protein
Nematode
AbI-related
elegans:
1. CeAbI:
protein
PFK-VII. Syk/Zap7O family vertebrate: 1. Syk: 2. Zap7O: Hydra vulgaris (Phylum
1. Htkl6:
*
PTK-VI1I.Jak
“Spleen
tyrosine
T-cell receptor
kinase”
“zeta chain-associated
protein of 70 kDa”
Cnidaria): Syk/Zap7O-related
family
vertebrate:
1. Tyk2: 2.Jakl:
Transducer
S. Jak2:
4.JakS:
*
of interferon
c/I3 signals
“Janus kinase”, type 1 “Janus kinase”, type 2 “Janus kinase”, type 3
Drosophila melanogaster: * l.Hop:
Product
of hopscotch
gene required
for establishing
segmental
body plan
PTK-lX. Ack vertebrate:
1. Ack:
*
“CDC42Hs-associated
kinase”
PTK-X. Fak vertebrate:
1. Fak:
“Focal adhesion
kinase”
PTK-XI. Epidermal growth factor receptor family vertebrate: 1. EGFR: Epidermal growth factor 2. ErbB2: Cell homolog of oncogene 3. ErbBS: Receptor tyrosine kinase 4. ErbB4: Receptor tyrosine kinase Drosophila melanogaster: 1. DER: Homolog of EGF receptor Caenorhabditis elegans: 1. LET-2S: Product of gene required Schistosoma mansoni (Phylum Platyhelminthes): 1. SER: EGF receptor homolog
PTK-XII. Eph/ElIc/Eck
receptor
receptor activated in ENU-induced related to EGFR (HERS) related to EGFR (Tyro2)
rat neuroblastoma
(Neu,
HER2)
for normal vulval development
family
vertebrate:
I. Eph: 2. Eck: S. Eek: 4. Hek:
5. Sek: 6. Elk: *
7. Hek2:
*
9. Cek5/Nuk: * * *
EUKARYOTIC
10.
11.Ehk2: 12.
PROTEIN
KINASE SUPERFAMILY
Kinase detected in “erythropoeitin-producing “Epithelial cell linase”
hepatoma”
Eph/Fik-related protein-tyrosine kinase Eph/Elk related protein-tyrosine kinase (Cek4) “Segmentally-expressed kinase” “Eph-like kinase” detected in brain “Human embryo kinase” type 2 (CeklO) “Hepatoma transmembrane kinase” “Chicken embryo kinase 5”/”Neural kinase” “Eph homology kinase-l” (Cek7) “Eph homology kinase-2” “Mammary-derived tyrosine kinase, type 1”
583
SERIAL REVIEW Table
1. (continued). * * * * * *
13. Myk2: 14. Cek9: 15. Pag16.Rtkl:
“Mammary.derived
17. 18.
Zebrafish EpWElk-related
protein-tyrosme
Zebrafish
protem-tyrosine
tyrosine kinase, type 2” embryo kinase 9” “Pagliaccio” Xenopus protein expression in neural crest and neural tissues Zebrafish Eph/Elk-related protein-tyrosme kinase “Chicken
Eph/Elk-related
kinase kinase
PTK-XIII. Axi family vertebrate: 1. Aid: *
“Anexelekto” (Cr. “uncontrolled”) tyrosine kinase (UFO, Ark) Cellular homolog of RPLSO avian oncoprotein (c-Ryk) “Brain tyrosine kinase”/”Sea related protein tyrosine kinase”/”Tyrosine and FN-III-like domains”/”Receptor sectaris” (TyroS)
2. Eyk: 3
PTK-XIV. Tie/Tek
kinase with Ig-like
family
vertebrate:
‘Tyrosine kinase with Ig and EGF homology” ‘Tumca interna endothelial cell kinase” (TIE2)
1. Tie: 2. Tek: PTK-XV. Platelet-derived A. Subfamily veitebrate: 1. 2. 3. 4. 5. B. Subfamily vertebrate: 1. 2. 3.
growth factor receptor
witih 5 Ig-like extracellular PDGFRa: PDGFR: CSFIR
Kit: Flk2: with 7 Ig-like extracellular
Platelet-derived growth factor receptor, type alpha Platelet-derived growth factor receptor, type beta Colony-stimulating factor-i receptor (c.Fms) Steel growth factor receptor “Fetal liver kinase-2” (FltS) domains “Fms-liketyrosinekinase”,type I “Fms-like tyrosine kinase”, type 4 “Fetal liver kinase-1” (KDR)
FILl: F1t4: FIkI:
PTK-XVI. Fibroblast
family
domains
growth
factor receptor
family
vertebrate:
1. FGFR1:
Fibroblast
2. FGFR2: S. FGFRS:
Fibroblast growth factor receptor,
4. FGFR4: Drosophila melanogaster: 1. DmFGFRI: *
2.DmFGFR2:
P1’K-XVII. Insulin receptor
growth
factor receptor,
Fibroblast Fibroblast
growth growth
factor receptor, factor receptor,
Fibroblast Fibroblast
growth growth
factor receptor factor receptor
type 1 (FIg, Cekl) type 2 (Bek, K-SAM, CekS) type S type 4 homolog, homolog,
type 1 type 2
family
vertebrate:
1. InsR: 2. IGF1R: S. IRR: Drosophila melanogaster: 1. DmInsR:
Insulin receptor Insulin-like growth factor receptor Insulin receptor-related protein Homolog
of insulin
receptor
PTK-XVIII. Ltk/Alk family vertebrate: 1. Ltk:
“Leukocyte “Anaplastic
*
PTK-X1X. Ros/Sev family vertebrate: 1. Ros: Drosophila melanogaster:
1. Sev: PTK-XX. Trk/Ror family vertebrate: 1. Trk: 2. TrkB: S. TrkC: 4. Ron: 5. Ror2:
6. TcRTK: Drosophila *
PTK-XXI. * *
584
Vol. 9
tyrosine kinase lymphoma kinase
of UR2 avian sarcoma
Cellular
homolog
Product
of sevenless gene required
virus oncoprotein
for R7 photoreceptor
cell development
High molecular weight nerve growth factor receptor Receptor for nrain-derivedneurotrophic factorand neurotrophin-4/5 Trk-related protein; receptor for neurotrophin-S “Ror” putative receptor, type I “Ror” putative receptor, type 2 Trk-related receptor (electric ray)
melanogaster:
1. Dror: Ddr/Tkt 1.
Putative
neurotrophic
receptor
family
2. Tkt:
May 1995
“Discoidin Domain Receptor” (TrkE, CAK, NEP, PtkS) “'Fyrosine Kinase Related to Trk” (Tyro 10)
The FASEB Journal
HANKS
AND
HUNTER
SERIAL REVIEW Table
1. (continued).
PTK-XXII. Hepatocyte growth factor receptor vertebrate: 1. 2. S. * 4.
HGFR: Sea:
Hepatocyte growth factor receptor (MET) Cellular homolog of SIS avian erythroleukemia
Ron: Stk:
“Recepteur
KinI5/l6 Caenorhabditis elegans: 1. CeKinl5: 2. CeKinl6:
membrane-spanning
tyrosine
kinase”
family PTK expressed during hypodermal PTK expressed during hypodermal
protein-tyrosine
vertebrate: 1. Ret: 2. Klg: * 5 Nyk/Ryk: Drosophila melanogaster I. Torso: 2. DmTrk: Marine sponge (Geodia cydonium): * 1. GCTK: Other
virus oncoprotein
d’Origine Nantaise”
“Stem cell-derived
PTK-XXIII. Nematode
Other
family
development development
kinases (each with no close relatives) Normal homolog of oncoprotein activated by recombination “Kinase-like gene” product “Novel tyrosine kinase-related protein” (VIK, Mrk, Nbtkl) Product
of torso gene required
for embryonic trk gene
anterior/posterior
Putative receptor
PTK
protein kinase families (not falling into m ajor groups) 0-I. Polo family vertebrate: 1. P1k: “Polo-like kinase” 2. Snk: “Serum-inducible kinase” * S. Sak: Polo-related kinase isolated in screen for genes regulating Drosophila melanogaster: I. Polo: Protein kinase homolog required for mitosis Saccharomyces cerevisiae: I. CdcS: Product of gene required for cell cycle progression 0-LI. MEE/STE7 family vertebrate: 1. MEKI: 2. MEK2: Drosophila melanogaster: 1. Dsorl: Saccharomyces cereoisiae: I. Ste7: 2. Pbs2: S. MkkI: 4. Mkk2: Schizo.saccharomyces pombe:
1. Byrl: 2. Wisi:
determination
Distant relative of the mammalian
sialylation
“MAP ERK Kinase”, type I “MAP ERK Kinase”, type 2
Kinase required for haploid-specific gene expression Kinase required for antibiotic drug resistance “MAP Kinase Kinase”, type 1 (suppresses lysis defect of pkcl mutant) “MAP Kinase Kinase”, type 2 (suppresses lysis defect of pkcl mutant)
Kinase that suppresses rasl-mutant sporulation defect Suppressor of cdc phenotype in triple mutant cdc2 5/wee i/win I strains
0-ILL. MEKK/SteI I family vertebrate: * 1. MEKK:
“MEK
Saccharomyces cerevisiae: 1. Stell: 2. Bckl: Schizosaccharomyces pombe: 1. Byr2: Phylum Angiospermophyta (Kingdom * 1. NPK1: O-IV. Pak/Ste2O family vertebrate: * 1. Pak:
Protein required for cell-type-specific “Bypass of C kinase” kinase Product of gene required Plantae): Flowering plant (tobacco)
“p21-(Cdc42/Rac)
Saccharomyces cerevisiae: 1. Ste2O:
Product
activated
of gene required
transcription
for pheromone homolog
signal transduction
of Bckl
kinase” for pheromone
response
0-V. NimA family vertebrate: 1. * 2. * S. * 4. * 5.
NekI: Nek2: NetS: Nrk2:
StkI:
Aspergillus nidulans: 1. NIMA: Drosophila melanogaster: 1. Fused:
EUKARYOTIC
NimA-related NimA-related NimA-related NimA-related NimA-related
kinase kinase kinase kinase
-
PROTEIN KINASE SUPERFAMILY
Cell cycle control Product
protein
of gene required
kinase for segment
polarity
585
SERIAL Table
REVIEW
1. (continued). Trjpanosoma brucei (Phylum I. NrkA: Saccharomyces cerevisaie: I. KinS:
Zoomastigina,
Putative
O-VJ. weel/miki family vertebrate: 1. WeelHu: Saccharomyces cerevisiae: * I. Schizosaccharomyces pombe: I.SpWeel: 2. MikI: O-VII. Family of kinases involved vertebrate: 1.HRI: 2. PKR: Saccharomyces cerevisiae: 1. Gcn2:
Kingdom Protoctista): Trypanosome protein protein
Gene product Weel
homolog
kinase related
to NimA
kinase
S. pombe wed
able to complement from budding
mutant
yeast
“Wee” size at division kinase; Cdc2 negative regulator “Mitosis inhibitory kinase”, negative regulator of Cdc2 in translational
control
“Heme-regulated
eukaryotic
“Double-stranded
RNA-dependent
Protein
required
initiation
factor 2a kinase”
kinase”
for translational
(Tik)
derepression
Raf family
0-VIlI.
vertebrate: I.Raf-i: 2. A-Raf:
Cellular homolog of retroviral oncogene product Oncogenic protein closely related to c-Raf Oncogenic protein closely related to c-R.af
3. B-Raf: Drosophila
melanogaster:
I. DmRaf:
Raf homolog
Caenorhabd it is elegans:
1. CeRaf: Phylum
Angiospermophyta 1. Ctrl:
Raf homolog; product (Kingdom
O-LX. Activin/TGF receptor family A. Subfamily of type I receptors vertebrate: 1. ActR-l: * 2. TSR-i: * 3.
4.
* *
6.
*
Drosophila melanogaster: * I. B. Subfamily of type II receptors vertebrate: 1.ActRII: 2.ActRIlB: 3.TG9IRII: *
*
Angiospermophyta 1. ZmPK1: 2. Srk: 3. TmkI: 4. Apki: 5. Nak: 6. Pro25: 7. Pto: 8. Tmkl 1: 9. PrkI:
0-Xl. Family of “mixed-lineage” vertebrate: * 1.MIki: * 2. M1k2: * 3. M1k3:
586
Vol. 9
Type II Type II Type II Putative
receptor for activin receptor for activin receptor TGFreceptor kinase expressed
in gonads
May 1995
homolog
regulatory
Product of gene required
O-X. Flowering plant putative receptor
*
for activin and TGF-[I (Tsk7L, SKR1, ALK-2) Type I receptor for activin and TGFG-1 (ALK-1) Type I receptor TGF- (ALK-5) Type I receptor for activin (ALK-4) Type I receptor for BMP-2 and BMP-4 (ALK.3) “Activin receptor-like kinase”, type 6
Larva development
C. Others Caenorhabditis elegana: 1. DAF- 1: Phylum
pathway
elegans:
i.DAF-4:
*
response
Type I receptor
Type II activin receptor
*
*
of ethylene
for vulval differentiation
melanogoster:
Caenorhabditis
*
regulator
of lin-45 gene required
Type I activin receptor homolog Product of saxophone gene
*
Drosophila
Plantae): Negative
(Kingdom
protein;
liMP receptor
for vulval development
kinase family Plantae): Putative receptor protein-serine kinase (maize) “S receptor kinase”; three distinct alleles: 2, 6, and 910 (Brassica) Putative “Transmembrane receptor kinase” (Arabidopsis) Kinase that phosphorylates Tyr, Ser, and Thr (Arabidopsis) “Novel Arabidopsis Kinase’ (Arabidopsis) Putative kinase selected for specificity to thylakoid membrane protein (Arabidopsis) Product of genen conferring pathogen resistance (tomato) Transmembrane protein with unusual kinase-like domain (Arabidopsis)
Pollen-expressed
receptor-like
putative kinase (Petunia)
kinases with leucine zipper domain “Mixed lineage “Mixed lineage “Mixed lineage
kinase”, type 1 kinase”, type 2 kinase”, typeS (PTK1,
The FASEB Journal
SPRK)
HANKS
AND
HUNTER
SERIAL Table
REVIEW
1. (continued).
0-XII. Casein kinase I family vertebrate: I. CK1a: 2. CKi: 3. CK1 4. CKI8: Saccharomyces cerevisiae:
Casein kinase I, Casein kinase I, Casein kinase I, Casein kinase I,
PKN
O-XiII.
2. Pkn2:
Fission yeast casein kinase I homolog, Fission yeast casein kinase I homolog,
7.LIMK:
(each with no known
*
Drosophila melanogaster: I. NinaC: 2. Pelle: * 3, Dictyostelium discoideum: 1. Sp1A: 2. Dpyk2: Ceratodon purpureus: (a moss)
1. PhyCer: Saccharomyces cerevisiae: 1.Cdc7: 2. CDCI5: 3. Vpsl5: 4. Nprl: 5. Elmi: 6. Irel: 7. Yk15i6: * 8. IpII: Schizosaccharomyces pombe: 1. Ran 1: 2. Chki: * S. CskI: *
type 2
type 1 type 2
protein kinases Myxobacteria: Kingdom Prohasyotae): Protein kinase homologous to eukaryotic Protein kinase required for maintenance
Other protein kinase family members vertebrate: I. Mos: 2. Pimi: S. Cot: 4. Esk: * 5. GC
6.Slk:
type I
pombe:
family of prokaryotic (Phylum
*
type delta
Budding Budding
Myxococcus xanthus I. Pknl:
*
type beta type gamma
yeast casein kinase I homolog, yeast casein kinase I homolog, Kinase required for DNA repair
1. Ycki: 2. Yck2: S. Hrr25: Schizosaccharosnyces * I. Hhpi: * 2. Hhp2:
type alpha
4. RPKI:
kinases of stationary
close relatives)
Cellular homolog of retroviral oncogene product Proto-oncogene activatedby murine leukemia virus Product of oncogene expressed in human thyroid carcinoma “Embryonal carcinoma STY kinase”; dual specificity (PIT) Kinase expressed in germinal center B cells STE2O-related kinase “UM motif-containing kinase” ‘Testis-specific kinase” Product Product Product
of gene essential of gene required of gene required
for photoreceptor function for dorsalventral polarity for rotation of photoreceptor
Spore lysis A protein kinase Developmentally-reguated tyrosine Putative
protein-tyrosine
“Cell-division-cycle”
kinase
control
kinase,
encoded
clusters
type 2 by a phytochrome
gene
gene product
“Cell-division-cycle” control gene product
Product of gene essential for sorting to lysosome-like Product Product Required Putative Product
vacuole of gene required for activity of ammonia-sensitive amino acid permeases of gene required for yeast-like cell morphology for Myo-inositol synthesis and signaling from ER to the nucleus protein kinase gene on chromosome XI of gene required for chromosome segregation
Product of gene required for normal meiotic function “Checkpoint Kinase” that links rad pathway to Cdc2 “Cyclin Suppressing Kinase” “Regulatory cell proliferation kinase”
Entamoeba histolytica (Phylum Rhizopoda, Kingdom Protoctista): 1. Ehmfkl: Distant relative of Mos Phylum Angiospernsophyta (Kingdom Plantae): 1. GmPK6: Protein kinase homolog (soybean) * 2. Tsl: Product of Tousled gene required for normal leaf/flower Yersinia psuedotubereulosis (Phylum Omnibacteria, Kingdom Prokaiyotae): 1. YpkA: Enterobacterial protein kinase essential for virulence
known primary structures. The kinase domains are further divided into 12 smaller subdomains (indicated by Roman numerals), defined as regions never interrupted by large amino acid insertions and containing characteristic patterns of conserved residues (consensus line in Fig. 1). Twelve kinase domain residues are recognized as being invariant or nearly invariant throughout the superfamily (conserved in over 95% of 370 sequences), and hence strongly implicated as playing essential roles in enzyme
EUKARYOTIC PROTEIN KINASE SUPERFAMILY
phase cells and development
development
(Arabidopsis)
function. Using the type a cAMP-dependent protein kinase catalytic subunit (PKA-Ca) as a reference point, these are equivalent to G1y50 and G1y52 in subdomain I, Lys72 in subdomain II, G1u91 in subdomain III, Aspl66 and Asnl7l in subdomain VIB, Asp184 and G1y186 in subdomain VII, G1u208 in subdomain VIII, Asp22O and G1y225 in subdomain IX, and Arg280 in subdomain XI. The patterns of amino acid residues found within subdomains VIB, VIII, and IX have been particularly well-conserved among the individual members of the dlif-
587
SERIAL
REVIEW
,uduain
I og-0-og-v
0 2”atruct
3
50
#{149}
b3
70
FIXTLGTGSFVIU,VYJUE fl8IIDrIV00FVELVQLSE PNFLMVIaXOSFGSVWLADRXO
130
SNI.YNVMEYVPG--GD(FSxL,SSIQR--HSDFIVRLYRTFSos KYLYCIa--0EL8ftI1.RaS--KPPFLTQLHSCFQTV osLYFEYW--0DUCfHIQQV--DCPFIWNSWHTP DSLSFILDU.80--ODuwrn,SQsaV--KHPFIVDLIvAFQ5 OXLYLILETLS0--OEI.FWQLI--NHPFVVXLNYAFQTE O.YLfl.DF10--0DLPTRLEVN--RWfl’QLHFAFQ NYLYLVY0--GDLL1’LLSKF0-F.HWIVP.LHDSIS OIU4YLIFDLV1’O--GELFEDIVAREY--N)NLIQLYAAIL’1’P HEIVLFWEYI--0ELTXVDEDyH-DHPNIIXVYPPPCrN NHYIFQDLIPO--ODLFSYLAxGDCI,TS 0HPNIIQLKYETh TFTPLVTDUX--0ELPDYLTExVT--YHPHIcRLFDCTLS NHFYWLFEYVS0--oQt.LDYIIQHOS--RHPHIIXLYDVIXSE DEIIMVIETTh0--NELFDyIvQRr--NNPWXVKFIQIYFEDS QNIYIVLELCXX--RS)e8ELHRXS--SHPNIVQFIDCFErO SNVYILLEICPN--OSI.J8ELLKRRKV--NH8IVKLLgJIHTE NYLVFEFU4Q---DLFW.SALTGRH8II0nDIIRAPTImN----KWYID1J’t---DLY5U.KTQH---DHQ8IVRLRYFFYSS0EDE---LYU4LVLEYVPE---TV’RVMHFTS,xL 0C8XIi’LADIvXvs RTPALVFENVNN--TDFXQLYQT TDPNSTFRCVQNLD4TEHH CHICXVFELLGL---STYDFIXE*IFLPDH8VIRYYCSET’1v RxLYIALEL.OIL---NLQDLVESIVSDE 0SSRVRPLCVR VIAVLPYYPH--EETRTTYRDRHDUMLYW.VL* ETVHLfl6EAa--0SVLLESC0P--RHWLN8VH4AVVPYiR,ELI.NDEVna1RCSDTLRTL,ADSWxQQxnlSE NSPYI’1DFYQAFYSD -0ElS!aEIa--0SLDQVLAaR--PICR8IITFYW.YflUfl8 NEIIII1lEYSDC--OSi.ILSVTKRFVQ ““21IV?YYCAS ‘4w ,an.nsr Ia.. yng--OWSSI2SY0PKHPNIVQYKESFED8 0SLYIVNDYC--0DLFXRflU.QkOALRHPNIVAYYHREHLRAS QDLYLYY--ODL8VIPSLKRThR XHPHVIIESFESX TDt.FVVTEFALN---OLHRYI.SYNOA--DHPNLPEFYCVYKLSKP!P----DEIWFVKEyCA0-GTAVVWLLKLDR X1CR8IIFIYV1 G.WVIMEYI0--OSLTDVVi’HCI---N)CR8IVXYHOFIRXS YYILLEYCAN--GSLRRLISRSSlv-NHPNIIETIEIVYn6 DRILQVNEYCEY---DI,FAIVNSNK---OPmVRL.LImP DSF Lfl.PEPV-QD(.PDFITER0ASHPYIITI.HRVLETE IYWi,QYCPN--0DLP’tYI?EKKWQQHSDICIIRL.WYEITD QyIyNV)4Eccau---DU8SWLYJCXKS8)NNVHIVRLILDSPFS ESIWIVT?RICSL--GELGIcRmDEDILP CHDHIVELHDSWEI GtYELC6--GSLFLEEQ0QLSR QHSHVVRYFSAWAED DIOLI8EYQlG--GSLADAI-S4YRIN DHVNIVHYNOCWDOFDYDPE(24 )KCLFI4EFCDK--OTLEQWIRRGEKNHQY RYYMWLEEDSND( 112) STFI4YCDJ--RTLYDLIHSnIUl-0GVGIPHIRWYGQ DYNvLVNDLLG---PSLmLfl8FCSRR-oHDnvsIF4oxrp PRPYLIMEFLDO--APLSAWVOTP NHPCIVXLLGINNPIFVTSX{14 ) PPCIS(IMSYCPA--ODL.LAAVNMNCR-RH(*8IVRVVAASTRTPACSN----SLCTID(EFOGN--VrLNQVIYDAAOHPE NNh*6LVRII*3FCS SILvSEYV6--OSL.MILFSEOosIL RH6ILALYGYSIK0 GCLVYQU0--OSLEARLRAHKAQNP EHn8II.FLThEXTEW EQS LITAFHAX--CRLQEYLTRHV---5582111.QflaA1](m’VSVD-----VD6.WtrIAFHEX--OSLSDFLXANV---REVNIL6.FWIY)ftK ItaI\rQWCm--SSLyxHLHVQETx-RHWVVQFLCACTACOE DHHCIvr5s30--OSLRQFLTvHFNLLE RHLVLYAWSE EPIYWrEYNSK--OSLWFLECrI’asYwHvcRLLaIctr SWQLITQLNPF-GCLLDYVREHm1PHU4VVNLLCACTIC OpxyIrrEycRy--oot.vvyuissxs’rFL NFPFLVXLEFSP#{216}8
of the eukaryotic protein kinase code is used and gaps are indicated
- -
--
superfamily.
The
by dashes.
The
are indicated as numbers in brackets. Twelve distinct The consensus line is given according to the following code: uppercase letters, invariant residues; o, positions conserving nonpolar residues; *, positions conserving polar
subdomams are indicated by Roman numerals. residues, lowercase residues nearly invariant residues; +, positions conserving small residues with near neutral and a-helices (a) in PKA-Ca are indicated in the 2- structure line.
The
III E--oo aC ----
QID1TLNEKRILQAv QQD4IRSQINQGA DVThVVLAI.LD FSVHP.IIORaomEVyoCpJr.an oL”nJ.LNI)a,sz.vsra FELLRVWY0Y0xV1QV9KV’1’GN8 DA14TKANILEEV FELLXVLGSFVFLVRKVTRPD osVRTmDILP,DV FEIuvIoRve.FSEVAwxQ EVSCFRDVLVNO YQLFIXGAFSWRRCVSVL DHQKLEREARICRLL 8SKEAI0mKF0AVCTCTS IVXLEIEVIO8QL Eli IVQTF0NVLITI*4SKERDEDVCY HP8YAVXIIXL KP8IPARILLRL YEPXEILGRGVSSVVRRCIHXP ?c5EmVxIID’,’ToooSFsAEEVQE----L.p.TLxEVDzLRKvs wErvrrvoAasMcKVKLpxHRY ThEVCAVKIVNRATKAFI,HXEQMLP( 20) RDSRTIREASLGQIL YQIVXTLOD3SFOKVKLAYHTT TOQEVALKIINXXVLAXSD NQtIEREISYLP.LL YIc.RMRFFCEQOFAXCYEIIDVE TD’I’VFAGKIVSXRLNIIHN QR(’rAQEITXHPSL, YHROHFLGSnOFMCFQIICDD SOEIFAAXTVMASIKSEK TRLLSEIQIHXS)( FQKVI0TYCVVY5ARNKt. 1’0EVVALIRLD’ElT VPS’rkIREISuzEL. YYI0AY4vCSkY8L N5VRVAIISPFEHQT YCQRTLREIKILLRF YTDIKVISF0VVYQARl1E TREI.vAIxxvLQ RFKNRELQD4RXL YQLVRXLOROKYSEVFEAINIr 1*OEXVVVXIt.XPV smxxsxixitnna IvurwMVVECAThfxA -OCR ‘151 VENV YCEMRSEIQVI,EHUIT WSIY0$S0’tVVPQ0SV QGRVAVXLID FCDIALSEIXLLTESD YKLII0i’FSSKAxDITGXITRIFASHfl*8Y0SNYVALIYVtS SPIYNEU8t.LYIWt NI0SIPA7CRVYLRQDIX TmMacspVD QFSDVEIQACF vwrverAmEsHISIIE’rR DKQRLVRXIERSIAE QHZ,FAEtEAY6IYR’PA0 FISEI40CVVFXVSP SCLVNMKLIHI,EIKPA IRNQIIRELQVLHEC LVQLIQ1S0TVVXALHVP DSKIVAXXTIPVEQNNST IflLVRELSIV8VK WLKGACIOSOSFGSVYL08O,11 I’GEIMAVXQVEIIO*8 IGVPT*( 35 )WVDM,QHnClU.XELYVR1QKICSFCRAVLVXSTE DORH’IVIICEINISRMSDR RQESRRAVLSNN yEvt,c.IOC0SFOIIRxvRRxs FILCRJ5EINYIXMSTI( ERraL.TAEFNIL,SSL. YAVSSLVGSF0CVyKATRKD DSKWAIKVIS0RATX EL6LRRECDIQARL, FSIYEEIAVNAXVFRAJtE1.D NDRIVALXIQHYD EEHQvSIEEEYRTLRDYC ThNL.VXI0ASOCVY’FAYEIG TNVSYAI5QtO6tQP KKIINEILV0S YHL.KQVICRGSYCWYRAIOU(H TDQWAIREVVYD8DE EUIDINAEISLLflOL IKi’GADLGA00SVXLAQRIS osxIFAVRzFRTKFIESKRD YV1ITSEYCI0TT1. yQv0PLL0500FGsvYsCIRvs osLPVAIKHVEXDRISn.P 9TRVPNEVVI.L,KXVSS LRFVSIIGACAYCVVYXAEDIY TLYAVRA1.CXmLNER QIcXLQAP.AL64ARvS YSILXQICSOOSSICVFQVLNE KXQImI51VNLEEAosQ ThDSYRNEIAYLNKLQ y’rLCVSAOSOQFCYVRVYSST LGXWAVRIIPPWNAQ0YSVNQV( 13) Ti*4S4EANRUO0IEXCRWE( FRNVTLLGSOEFSEVFQVEDPVE STLXYAVIuL.SVKFSCPK R)LLEVSIQRALJC FHELIGS0EFCSVFXOCR.L oscIYAISKJLA0SV DW4ALREVIAMAVW FXEIELIGSQCFCQvFPXHRI DCXTYVIERVKY NNflCAEREVKALARI. LKRL,NFS000AFOQVVKARNAL DSRYYAIIQ(IRNFEE KLS1NISEV)4LL.ASL YKLVRXI050SFCDIYLAINIT NCEVIAVKL.ESQKA RHPQLI.YESXLYKILQ FRLVRRLOROGNCAVYLCEHVS IGSRVAVXVI.HAHLTNYPE L.VQRFHAEARAVNLI WKJCVRPICSGNFSTVLLYEI14DQSNP xLxQvAvxxu(YPEEL,SNVEQINrSL( 8) 16SLTREt,QVt.XS1, VCLLQRLGAOGF0SVYXMYR CVPVAIKQVNXCTD(RLA SRRSFWAEU8VARL RRFICVELGRCESCTVYKGVLE DORHVAVER.L6VRQ GKEVFQAZI,SVIORI WSPLGGF0DVYR0KWX Q1.DVAIKV)*IYRSPNZDQ4V ELQQSYNELKY11SI IELDTLv0IuRFAEVYKAXLXQN’FSE QFETVAVRIFPYDHY AS9DRIFSDINL IQLLEVXARORFOQVWKAQI.LN EYVAVXIFPIQDK QSNEYEVYSLPCN VNLSTRICa3SOGTVU0KS1H ODVAVKILKVVDPTPE QFQAFRNEVAVLRRT LEFGQTI0K0FF0EVXR0Y0E TDVAIKIIYRDQFXTXS SL.VNFQNEVOILSKL 1JLEVXLOCFGE7WI0 RvAIxt.xpoTw SPERFLQEAQV)OCUa FXIKvLGmAFC’rvyxc(aWIPmEI( VRIPVAIKELREAISPX ANKEILDEAYVMASV LVLGRTLGmAFGQWEATAHOLSHSQ ATMKVAVIO6LKSTARSS EXQ9.LNSELXIMSHLG
Figure 1. abbreviated
entire
II oaoX-o
b2-,
-
residues
polarity. Residues corresponding
to the numbered
n-strands
(b)
ture was revealed for the first time (25, 26). Later, structures of ternary complexes of PKA-Ca, the pseudosubstrate inhibitor, and either MgATP or MnAMP-PNP (an MgATP analog) were solved (27, 28). As a consequence of these studies, precise functional roles for most of the highly conserved kinase domain residues have now been assigned. The kinase domain of PKA-Ca folds into a two-lobed structure (Fig. 2). The smaller, NH2terminal lobe, which includes subdomains I-IV, is primarily involved in anchoring and orienting the nucleotide. This lobe has a predominantly antiparallel f-sheet structure that is unique among nucleotide binding proteins. The larger COOH-terminal lobe, which includes subdomains VIA-XI, is largely responsible for binding the peptide substrate and initiating phosphotransfer. It is predominantly a-helical in content. Subdomain V residues span
The FASEB Journal
HANKS
AND
HUNTER
SERIAL REVIEW gubdui,ain
VIA
PER-Cu PRO-I cPKCU MaRl SEE 5151 (Nt) DPEN Ca552u .kNLCR Nr.4 PhR5N 5101 Sot 1
Polo Cdc5 Cdk2 k2 0SR3u C12a Clk 11.1 Cdc7 Cot YpkA NER1 Sta7 Stall NINA Fua.d NIOaC Sta2O CdclS 91*1 Ranl Eak Elmi Skis 16 SpWa.l W..1 (KB) PER Gcn2 CElu 99581 NOB 2*951 Pall. ‘NFRII AcIRII Rat-i Sp1A Src 8flFR PDGPRB
Figure
VIB VII VIII o--,o-ooh oohrDok,-N000 okc.Dfgo g.--o-.pEooaE ,b6o < b7 b8 sb9 140 150 160 170 180 190 200 210 FSEPHARFTAAQIVI.ITETLNSL OL.IYRDL.XP8LLIDQQ OYIQVTDFOFAVKO ESWrLOCTPEYLAPEIXFWSTIRFTThCVVEAFAYLHSK -OIIYRDLn8LIL.DHR CYAILVDFOFAXKIOFCR KnftTCCTPEYVAPrIIFXEPQAVFThAEISIOLFFLHER -OIIYRDLID.ftM6LDSE OHIKIADFWOO8osV T’irTOC?PDYIAPEIIFSEFYAAEIILGLflOO* FVVYRDL.5NILLD4 GHVRXSDLGL.ACDFSU RPNASTHQYNAPEVLQ FNEDTAcFYIAEISNALOHI,HQR -GIIYRDLKPlIXUIHQ OHVRLTDFGLCEESIHosT VThTFOC’EIEYIU.PEILFTEEUJXFYLAELAIOL6LHSL -OIIYRDLn8IU.D OHIXLTDF0LSKEAIDH KAYSTOCTVEYNAPEWXPA8ARFYLAEIVNAXDSVHRL -GYVHRDI8ILLDRC OHIRLADFGSCLn.ERusrv RSLVA’.TPDYLSPEILQ YSSHCIQQILAVU4CH 0DLD8LL.LASELX0 AAVK1ADF01.AIEVmQ AWTOFAOTPUYLSPEVLLTEVMI(VFVRQICILFWU RVLNLDLPlILCWrr1’0 HLVXIIDFOIaARRYNP8IE KIVNF0TPULSPEVV NSETESLLIVFQItOAU8YLH -OIVHRDLKLlILLCTPEPC TR1VLADFGIAXDU8S8E RIC1TVTPEYCAPEV0F LSnXIIALLEVICALH NIVHRDL.KPDIILLDm )OIIKLTDF0FSCQLDE ktaZVca?PSYI.APEIIE IRENQARXFAPCIASALIYLHAZI NIVHRDLX1D8INIS SEUIIDF0L8IYDSRE QLHTFcOSLYTAAPELLNSEQEARRFFQQIISAVEYCHRM KIDLDlU.LD6 u6VxIADFGLSNIwr8 ITETEcRYYIYQIIQ0VXYLH4 RIIHRDLILFU4DL LHVXI0DFOLATR1EYE RTLCGTMlYIAP!ILLTEPEVRrFrYQICGAIXYNHSR RvflDLEIFFDi YNLKIoDFoi,AAV1NEsE RKY?IOCTPNTXAPSVIJ IPLPLIISYI.ZQLLQOL.AFCHSH RVLIDLKP8LLI19rE CAXXIADFQLARAICVPVR T3TNEVVTU6YRAPEILL L8ICYFLYQI(50LEYIHSA NVLHROLEPSNSSUITF CmEICDFGLARW.DP4DIn FLTEYVA’I’RWTRAPZINL IPIIYVEVfl1YQt.FRSLAYIHSQ -OVCDIKPILLVDPDT AVLKIDF0SAXQLVRQE P8IVSYICSRYYRAPELIF 1.TDYDnFY11YEItALDYCHSM -OINDVIPI*lVNIDHEH REl.RLILAE?YHPOQ EYNVRVASRYFXQPEL,LV FRLCHnnU,YQIcESVNVLNaO ELTH?DLD8ILFVQSDYTEA( 14) PDIXWDFGSATYDOE HHSTLVSTRKYRAPSVIL QREYNPIS1.IQIAS0vAHLHSL XIfleDLKP1ILVS’rSSR?rAD(7 ) LRILISDFOLCXRLDSQQSSFRT NU*IPTSAPELLLPIXOIUYIWELISALKFVHSR -OIIHRDIXPTNPLFNI.EL GVLVDF0LAEAQNDYXSNISS8DYA18(72 )AJaNRAG5RGFRAPEVI IE7EIIWVTEHVIZ0t.LHSX EVIHHDISNIVTNS TXAVLVDF0LSV6TEPY FWDLTEIYNSPEVIAYTIUIAHRLWV’1’NHLAXA -OW)*8DIKPQlVVFAS OWIDLQt,NSRS GPXOFrESPRAPEI4V IPEQIiVSIAVIIGLTYLRH RINNRDVXPSNILVNSR OEIRLCDFGVSQQLIDS NMISTTRSYWSP.LFNELTISXIAY0VULLYRQY EIIIOISNVLINSX GQIXLCDFCVSINS IAI’TlTSTYNSP.IFUSL.INPiQItI0VAYLffI NIIIDIXGARILIDIX OCVRITDF0IS.SPUl ERMLQQSVPlSP!VVFQEDQILIFVQICLALXHVH KILHRDIXS8IFLTEDCTVQWDFGIARVU8STVZ LARTCIOTPYYLSPEICAFVWRILSQLVTALYRCHSGTDPAEV0SNLL(i6)Tfl,HRDLD(IFL0SDNTVKWDFOLSY.U8HSHDFASTY?PFYNSPEICIEEPARRViuNtVSAtYYL.HSN 511 DL gWVLL.O8 NHAEI.CDFOLAmI8TIOTI4 VLTSIKQTPLYNAPELLzEHIAyIIRETcRAAIELNsN Hfl.HROIRG8ILLTIQ8 GRVXLCDFOI.SRQVDSTW TCI0SPC8SIAPEVVS LTQICAVETLSGLDLHSE OVUeDXxS8XLt.SNE ODIXLTDFOFCAQINEU8L T’IiTPiIW.PEVVLSDIETYVTQTLLOL5Y1aHOE GIHRDIKAMILLSAD NTVKLADFOVS3’IVNS SALTLSGTUu*85?EXLNSYEEICCCPIQILTOVQYLHSI -G(DLxL.cvnOC( GIvKLIDFCRAvVFSYPFSu8Lv EAS0I’SDPTLAPEVCI LQEEWRSFFWQVLEAVRHCIQ CVL)6DIKDIILIDUIR OKLIDFOS0AL.L.KD V57DFTRVYSPPEWIR Q8SHtIKTVT1.QLISAVElCHSV 015 DUPu6IWVONDG NTVYI,ADFGLADFEPY SSDFOCOSLFYXSPECQR IXSY4LEAVHTIHQH -GIVHSDLKPA28FLIVD0M.XLIDFOIAN4QP0TTSV VRDSQVOTVNYWPPEAIK SVSTFAILmrtRGLEYLHSQ -OcIHRDInSNILLDEEE xx1,SDFGSCIFrPQSLP?SDANOtDCFQR----Eu8KIVDTPAFIAPELcH L.EAWLIQRIFTEVVLAVKYLHDI SIIHRDL1ILLXYSFDDIN(11)NFIELADF0LCXKID*8E NCrARCGSEDYV5PEILN IDEFRVWKILVEVAIOLQFIHIU( NYVHLDLXPANVMI3’FE G’I’LEIODFCuASWPVP R6ERDCEYIAPEVLFEEAELKDLLLQVCRCt.RYIHSN SLVHNDIXPSNIFISRTSIPNA( 14 )VI*XIODLGHVTRIS SPQVE9DS9FLA28EVLQ LCRVLAI.ELFEQIIEOVDYIHSX KLIHRDLEPSNIFLVDt KQVXI0DF0LVSSL8m KRTRSWTI.RYNSPEQIQQRDESWRLFRQILEAL.SYXHSQ GIIHRDLKPIIFIDES RNVKI0DF01IVHRSLDIIDS8LPGSS8--LLTSAI0TANYVATEVLD #{163}ISIETVUILAQQNISRIEYVHTR NFIHPDIXP8FLbIGRHC NFLIDFGLAXXYRTRQHIPYR E6LITARYASD8A14L LAACAWSVLSQVCLQAAHAR -0flfleDLXPIFLVRR0 PFVKVLDFGIAXLADUOWQT IUII1i’PEYwAPEQSLS1CLXYSLDVVTLLFLHSQ SIVNI.DL.KPMILIS DVCXISDFOCSEn.EDLLCFQT PSYPLTYi’HRAPELLI.JRFNIA1aVARC1AYLHHECl.E WIHCDVn6IL.i.DQA FEPKI’i’DF0LVXLU6ROCSI’QNvSHVTLOYIAPVL.ISIQQRFSISLCTARCIYFLHIS.RCT PLINIDIKPA28IL.LDQC LQPKIODFGLVRxoPKSLDAW EVNXVSDTKIYLPPEFRI6EDI5NSSLM0LSHLHSDHTPCORPflI PIVmDLxSSNILV6D LTCCLcDFcLSL.RIPYSSVmL Ass0Q’rARyxAPEV1.E VS1*lEICHIAEi4AP0LAYLHIPGLROCHKP AISHRDIRSlVL.L*8 LTACIADF0LALER.SAODTHOQ’,TRRYNAPEVt.E PFQLXDIERQTAQONDYLHAx NIIHRxSomIFu1m LTVEIODF0LATVXSRWSOSQQVEQPSuSVUdWAPEVIR 8pHIRL.ALDIAx.wLHerP PIt DLSS nLLc.a61c5’nue) IKcKI5DFGLSRLKXEQM QNTQSS*CIPYXAPEVFLRLPQLVAAQIAS0NAYVERN NYVHRDLRAANILV0I I.VCxVADFmARLIEIEYT AkQOAXFPITAP!AAI0SQYLLN9VQIAXOIO8YLECR RLVNADLAARNVI.VXTP QHVEn’D}0LAxLI4AEY HA0EVPIflUIALESI74) I.SYMDLVQFSYQVAN0MLASX NCVDLAAP38VLIC ELVKICDFCLARDINRDSNYX EROS LPL,flS8APESZo
cona.o.u. 2.truct
I
S a
1ERXvISI
SY
CDHCR1QWA
QHHS(RRPPSAELYu6ALPVG(
1 (contd.).
the two lobes. The deep cleft between the two lobes is recognized as the site of catalysis. The crystal structures of four additional eukaryotic protein kinase superfamily members-cyclin-dependent kinase 2 (Cdk2) (29), p42 MAP kinase (Erk2) (30), twitchin kinase (31), and casein kinase I (32)-have been reported more recently, and as expected, their kinase domains were found to fold into two-lobed structures topologically very similar to the catalytic core of PKA-Cct. Notable differences, however, were found in the regions corresponding to subdomain VIII in the Cdk2 and Erk2 structures, apparently reflecting the fact that these are structures of enzymes in an inactive state (see below). The twitchin structure is also of an inactive enzyme, but in this case it is inactive due to the presence of an autoinhibitory peptide sequence, which lies on the COOH-terminal side of the kinase domain and folds back into the active site cleft between the two lobes (31). This peptide apparently forces the two
EUKARYOTIC
PROTEIN
KINASE SUPERFAMILY
lobes to rotate almost 30#{176} with respect to one another, and in this configuration inactive twitchin is more similar to the open configuration of PKA-Ca without PKI (33). In both twitchin and Cdk2 the a-helix C in subdomain III also adopts a different position to that of helix C in PKA-Ca. Unfortunately, no structure of a protein-tyrosine kinase catalytic domain was available at the time of writing (see “Note added in proof”), but the ease with which it has been possible to model the kinase domain of the EGF receptor protein-tyrosine kinase on to that of the PKA-Ca emphasizes that the structure of the protein-tyrosine kinases will be similar to that of the protein-serine kinases (34) The conserved kinase subdomains correspond quite well to precise units of higher order structure. The functions
of
the
individual
subdomains
briefly later on a subdomain.-by-subdomain ing reference to the crystal structure
will
be
discussed mak-
basis, of PKA-Ca
and
589
SERIAL REVIEW
PEA-Cu P50-I CPRCU MaRl SEX REEl (Nt) IPR Ca1652u PhX7I6 Kial Sntl Polo C4c5 CdkI Erk2 0553* 0(2* Cik Ir.l C4c7 Cot YpkA Sta7 st.t1 N.kl NINA Yua.d Nin*C StaSO COalS Spri 91*1 Ranl Elk 51*1 Yk1516 SpWa.i Sisal (H.) PER OcnS CElu Pknl No. 2*951 9.11. TOFRII ActRil Rat-i SplA ETC
ROTE
Figure
X
IX
uabdca,ain con..ua 2”.truCt
PC
0
aF 220 230 240 LSRGNE-AV*1aVLIYAA-OYPP?FA UIEGNDI-SADYWSIOIUIYELLT-OSPPTm AYQPYCR-SVuY*VLLYEIIA-OQPPTm EAYDS-SAIWFSLOcNLFRU&-OKSPFRQHX NERO R-AV(SLOAU(YlRlLT-GAPPF’1u
XI
aO 250 DQPIQIYXV-RV-RFPSN PDPWTYNIILIaERPER ROE.FQSIII-NV-SYPRS TKIEIWrLi18AV-95.PDS DlRERTIILXC5L--NLPPY
270
280
>
90
LsxrAvsxcROueIlpAERwcGp.DPpE--Ks.Fv t,TQEARDU.LLMASRLQAGPaEVQA--HPFP
,
AV(4 )Q5SYOP-ECWVTAYlFY-QQTPFYA
DSTAETYCRIVHYXEIO.SZ.PLVDRO 5509505-P FrLMACOVILYILLV-OYPPFWD EDQILYQQI51AYDPPSPDIDT R( 15 )EQRQYDS-XCWSLaVIThINLT-0ISP6!aD------OSERSIII1,xICXU6TkLKIDI CSNEIHP00R-EV5lS2VIJlYTLIA-0SPPPW REQ U(LRNINSlYQF0SPlDD KM1PYTOPE,WWSPVVLFIfl.VC-OXVPFm 956SSVLHERIRXV--EYPQH SOxLYAGPEVWWSOCVILYWZ-RRLPF ESIPVLm8IuVY--TLPRF TERIST-EVDIWSI0CVWYTLLV-0QPPFET RTLW1’YSRIERCEY--RVPSY O----KN9OKSF-EVDIWSWVWLTAI.LI-OEFPFQR RDv),FIYNEIXcRDF--SFPRCRP -----0CXYYST-AVDIWSIOCIFA6’1E-RBALFPGDSEI---DQLFRIFRTWTPDEE-VWROVTlPDY5P5TP NSxGYTX-SIDIWS50CI1AI,S-NRPIFRORHYL---DQUu6XL0ILGSPSQE-DU8-CIDIL59A18TLLSLPN95I5VPWLFW -----OA?VYTS-SID’,’WSAOCVLAELLL-OQFIFRODSGV---DQLVEIIRVLOTPTRE-QIR-DIIPWYItTR?PQIXAH---WIEVFESR
XNERQDTSRVVPP
5(24 )T55PLTR-5IDIFS)UCVTYYILS5095lPFY SREuIIIR0IFSLDCL16S KCQAQST-KIDIWS%VILLSLLO-RRFPW?QSL WR6ST-5ADITS1A?LIlOQr-0TPPWVE RYPRSATPSYLYIIHKQAPPLEDIAED -----lZASE-XSDPFLWSTLLHCIZ-GTm6PEI5P----NQQIFITSEPAJIVl95TPINRP0I?a Q0FtffSV-QSDWLSt.VlAV-ORYPIPPP(36)RPPNEIFnDTIVNEFPP95.PSGV QlVYSI-56lISLaIMIIELVr-OEFPIIaI DTPmfl..LQRIPSPRLPI 5QTAirA-KADIWS1ucVI69’T-6PFPDF SQNQAIFRIOIIITTPERPSW DffPYISI-ESDINEWCVLY01.CT-LEHAFER -G5qLV1XI90SFPPVSPH AATL-RSOINE”CINYELCQ-REFPFNE RT0IQLVIRED5FAPLPOT AD!PTI-HAalSIaCIAYESW.OQPPFCA SSILHLVThIKHEDVUIP95 AsE--sEPDITv-RA1aI11ELAD-osPPFAHpr---RAsFQIIIpPPTLathPm SRR5Y0P-XDIWStaINIID(IE-OEFPTI28ETPL---RALYLIA1iTPXLkEF8 -----ROT-LSDIWSLGATWD6LT-IPPYIII L1NITTAV016DTTYPPSS FAxYDPR-PVDIWSSAIIFAC1tIL-PWRIP5l---rR1SFKLFCSORDCDSLSSLVrRTP0PPSYDESflSTRE5XPESS5lVSDP1*lVNIQPQ(5 YHRYH0R-SAWWSWXLLYlYC-ODIPF D1DERIIROQVTFVQR 5(24 )SSSERTA-PSIWWAIOIILDILCC-RPNPWR RACSQTDOTYRSSVNNPSTLLSILP DI( 6 }CRSKISP-XSDYWS6OCILYYWTY-OXTPFQQXI NQISKLHAIIDRNHEIEFPDIP W(4)DFVTF-RLDIWSLaVTLTCLLY-NELPFPGuIff---ETYHKIIEVSL.SSRIN -----PYH-LSD’11WVILYSLFE-LPFDPPPNE(7 )ATSNRIMIUIuIYRLSD AJINLY05-PADIFSWITVFEMA--NIVLP69I -OQSRt.RS0DLSPRLSST95SSLTSSSRETPA1ISII 9rINLP-XADIFA1ALTVVCAPO-ALPLPFN -0DuIEIRQLPRIPQV SSQDYOX-EVmYAIOLILAELLH- --VCD’rA FEFSKFP”!VLREDIISDI -- ---0 GHiI6E-5IlYSLOIIFFD6IY---PFSTO NVNILXXLRSVSIEFPPDPD69 0IEQSR--RDalEStW1UNE-TgL9WQOLKAATLRQCIERISREsTPVEVLcROFPAEFAI4 LOROVDO-RArLTALGVIATQLLT-ORLPFNDE -OL.AAQLVAHQLRPPPPPSSVYPA 5QROr9p-KADIYSFAITu8QItfl-KQAPYS -OQHILYAVVAYDL,RPSLSAAVFEDSL SSLPITA-RVD1YSS0VVLLEX.LT-GTRVSELV -OGT05VHSNIPXLVRIU.SAEt.ROEEQSWImTLDSJIS1RPVNYV NFRQLsT-OvwysmIvLLEvFT-oRQvTCRvPul---El’T8u.DYv5QQwR6R001.LER1lLAAP1xELD SRJC8-LDIAZSFRQTWYSIV.LVINDIT( 13 )PPFOS XVRDPVVESNEIWVLRCROTRNSS-FWUIHQ ON-TQR-W.FIaIOlIYAIGLVIMELA( 14 )LPFEEE I0QHPSLIQEVYVH5ERRPVLRDY8HA --NQ-OlSIPFSF-QSDPTSSOIVLYEIM9-O01.PYSNI 1EIRIIPIEIYASPDLSKLY958 50DlSE-XSD’lYSYGIlVLFELLT-S05PQ6 XPIROIAHLAATESYRPPIPLT LYORFTI-XSDPWSFOILLTELTTKORVPYSO NVNREVLVTRI69CPPE LxRIy’r16-oswwmvTvwExMryosxPTm IPASEISSILERLPOPPI
‘195 ARD?ILLC-PPETRLOCAGDFRT----HPFF V7PE5ROLDNLTINPSERITAAEALE VSX2T TDVVKRUXQ0LK TED’s’ 50LVR5FLWQPCRYThEEAI,A LSIEVISLLILVVDPURATLKQVVE LSP0ALI1CaIVNPU4RISIHED8Q LRXPMlVIANLQPNPESRPAI0QLUI ISDROEILIRDILSLDPXREPSLTEUID LRSLLs6LNYDEWIRIS51AM.A ACuI(AWLL(NLT?NPH5RIEVEQALA TPP95.IALCSSLLETEPSSRLSPL,EACA VSP!AWFLAY6Q8RLT51EANE
169111 KIWI HPFT HHI DIF FEFL. YVOff NPFT 0901. HEFT 09SF 169FF HP1Z 59FF HR.L HEFt. HASY HDLI 0915. ROT! SPY! HPFV HPFL DETI NW! PFWI HP8 LVu8 169W VLSR SPFV
LIAEATDLIRII8DPL5RPMjVLR }6YWCTQVL!QCFIDPSSAEDLLK CSPlR.ISLNP0UIRPRAADL.L5 VLTATIEFITDIIOVSAIWRPDSNEARL TSLE DOT lCLROlPAA.5QUlV TtE8FTDFVNECCmIERERSSIKELLN ATSlFL55AF01.DYQYRPSAI.ELLQ TSYDt.RSLLSQLT)IPRPSVNSILE TREE IVIASCL PIRPD?ATLIW LTCECRSFLDO1.LDPosITQZ.LC WSQQI0FISESLIADPIIWu.VE LSS8LER.FLD’ACLCVEP.ASATELUI F9EPL50FLCTVIOOITERP17DQLL5 )LPEETQHIIULLAPACR6IEEII6E VSSQHLZ11L8LRPS05P’rFEEIQN ISRSU6SLUmIFNPRTRIThPELS? EKDDLQOVLECCLICRDPKQRISIPEU.A ITu6r*.VImLssDVTLRIsIQoLVR YRT?IV05QIV8TLTRfl6QRWSINEIYE 0Q00LCRVV56I.SPEPRNRPI’IDQILATD-----EVCW LSQEF1’EL.LXVNIHPDPRPSAMALVR HEW. F05xru.OTI5.S55PPpSrSEILR TLTV 955tVIIRLLIt96DP1U(RPGARTU1I SOlE. YUIYCROLRFEEF.POYXYI.RQLFRILFRTUINQY-DDIY VSAALE WIt ALRERPERSTASIAAFPNAI.----QVAL #OQRLOCVICWRPSAAQRPSARLL.LV DLI’S QARTLIRLAVSCLm*SKRPSNEHA SQl’S. NcNCAIEAOUIC?AWPQCRPuIIAVL51.F EPFV OIQNVCETLTW1DPRERLTAQCVAERPSE---LEHL OlJcCETI55CW1CuRLSAOC195ERITQ---HQPL CPRAI.LV7,DCVERV5PS.FPQILSSIELLQ-HSL.P ?SS95I55ILTQCWNPDPRPTTRQI IVOL CPESLHDLWIQCWRXEP.PTFEYL QAFL CTI 610 KCWWIDADSRPFTREL IIEF
1 (contd.).
attention to the proposed roles of the nearly invariant amino acid residues (25-27, 28) and other residues of interest. For more detailed information, the reader is referred to recent reviews on the structure of PKA-Ca (35-37) and to an excellent comparative review of the structures of PKA-Ca, Erk2, and Cdk2 (38). Subdomain I, at the NH2 terminus of the kinase domain, contains the consensus motif Gly-x-GIy-x-x-Glyx-Val (starting with G1y50 in PKA-Ca). The kinase domain NH2-terminal boundary occurs seven positions upstream of the first glycine in the consensus, where a hydrophobic residue is usually found. Subdomain I residues fold into a 13-strand-turn-f3-strand structure encompassing 13-strands 1 and 2, and this structure acts as a flexible flap or clamp that covers and anchors the nontransferable phosphates of ATP. The backbone amides of Ser53, Phe54, and Gly55 form hydrogen bonds with ATP 13- phosphate oxygens. Leu49 and Val57 contribute to a hydrophobic pocket that encloses the adenine ring of ATP. drawing
590
aN
o
5-
00--Co
0
