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• W1993990713 abstract "The vast majority of eukaryotic protein kinases have a similar catalytic domain structure consisting of twelve conserved subdomains [[1]Hanks SK Hunter T Protein kinases VI. The eukaryotic protein kinase superfamily: kinase (catalytic) domain structure and classification.FASEB J. 1995; 9: 576-596Crossref PubMed Scopus (2194) Google Scholar]. We, and others, have recently reported the existence in eukaryotes of protein kinases with a completely different structure [2Côté GP Luo X Murphy MB Egelhoff TT Mapping of the novel protein kinase catalytic domain of Dictyostelium myosin II heavy chain kinase A.J Biol Chem. 1997; 272: 6846-6849Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar, 3Futey LM Medley QG Côté GP Egelhoff TT Structural analysis of myosin heavy chain kinase A from Dictyostelium. Evidence for a highly divergent protein kinase domain, an amino-terminal coiled-coil domain and a domain homologous to the β-subunit of heterotrimeric G proteins.J Biol Chem. 1995; 270: 523-529Crossref PubMed Scopus (75) Google Scholar, 4Redpath NT Price NT Proud CG Cloning and expression of cDNA encoding protein synthesis elongation factor-2 kinase.J Biol Chem. 1996; 271: 17547-17554Crossref PubMed Scopus (65) Google Scholar, 5Ryazanov AG Ward MD Mendola CE Pavur KS Dorovkov MV Wiedmann M et al.Identification of a new class of protein kinases represented by eukaryotic elongation factor-2 kinase.Proc Natl Acad Sci USA. 1997; 94: 4884-4889Crossref PubMed Scopus (156) Google Scholar]. We cloned and sequenced cDNAs encoding elongation factor-2 kinase (eEF-2 kinase) [[5]Ryazanov AG Ward MD Mendola CE Pavur KS Dorovkov MV Wiedmann M et al.Identification of a new class of protein kinases represented by eukaryotic elongation factor-2 kinase.Proc Natl Acad Sci USA. 1997; 94: 4884-4889Crossref PubMed Scopus (156) Google Scholar], a ubiquitous protein kinase involved in the regulation of protein synthesis [[6]Ryazanov AG Shestakova EA Natapov PG Phosphorylation of elongation factor 2 by EF-2 kinase affects rate of translation.Nature. 1988; 334: 170-173Crossref PubMed Scopus (327) Google Scholar]. The catalytic domain of eEF-2 kinase does not display any homology to the catalytic domains of the conventional eukaryotic protein kinases [[5]Ryazanov AG Ward MD Mendola CE Pavur KS Dorovkov MV Wiedmann M et al.Identification of a new class of protein kinases represented by eukaryotic elongation factor-2 kinase.Proc Natl Acad Sci USA. 1997; 94: 4884-4889Crossref PubMed Scopus (156) Google Scholar]. It is, however, strikingly similar to the catalytic domain of myosin heavy chain kinase A (MHCK A) from Dictyostelium[2Côté GP Luo X Murphy MB Egelhoff TT Mapping of the novel protein kinase catalytic domain of Dictyostelium myosin II heavy chain kinase A.J Biol Chem. 1997; 272: 6846-6849Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar, 3Futey LM Medley QG Côté GP Egelhoff TT Structural analysis of myosin heavy chain kinase A from Dictyostelium. Evidence for a highly divergent protein kinase domain, an amino-terminal coiled-coil domain and a domain homologous to the β-subunit of heterotrimeric G proteins.J Biol Chem. 1995; 270: 523-529Crossref PubMed Scopus (75) Google Scholar]. In order to analyze how widespread this novel class of protein kinases is, we performed extensive database searches for proteins with homology to the eEF-2 kinase/MHCK A catalytic domain. No homologous proteins were found in any prokaryotic organisms or in unicellular eukaryotes, including Saccharomyces cerevisiae, the genome of which has now been completely sequenced. Similarly, this type of protein kinase catalytic domain has not yet been detected among plant proteins. In Caenorhabditis elegans, the genome of which is almost completely sequenced, only one such protein has been found, and it is eEF-2 kinase itself. In Dictyostelium, there are at least three proteins that have a strong similarity to the eEF-2 kinase catalytic domain, two of which are MHCK A and a protein kinase called MHCK B, which can also phosphorylate myosin heavy chains in vitro[[7]Clancy CE Mendoza MG Naismith TV Kolman MF Egelhoff TT Identification of a protein kinase from Dictyostelium with homology to the novel catalytic domain of myosin heavy chain kinase A.J Biol Chem. 1997; 272: 11812-11815Crossref PubMed Scopus (44) Google Scholar]. The third protein was recently identified from a genetic screen for morphological mutants (W.F. Loomis, personal communication) in which the disrupted gene was named mhkC (GenBank accession number AF079447). The physiological substrate for MhkC is as yet unknown. In searching the mouse and human expressed sequence tag (EST) databases, we identified several ESTs with homology to the eEF-2 kinase/MHCK A catalytic domain. Clones corresponding to these ESTs were sequenced. The sequences obtained were used to search the EST database for overlapping clones, and the longest of these were sequenced. From this analysis, it became clear that, in mammals, there are at least three more proteins with a strong similarity to the eEF-2 kinase catalytic domain. We named two of these proteins ‘heart kinase’ and ‘melanoma kinase’ because the corresponding EST clones were from mouse heart and mouse melanoma cDNA libraries, respectively. The third protein we named ‘chromosome 4 kinase’ because we found that one of the bacterial articificial chromosome (BAC) clones of human genomic DNA from chromosome 4, the sequence of which was recently deposited in GenBank, contained the gene for this protein. The new sequences enabled us to identify the consensus sequence of this novel type of protein kinase catalytic domain. An alignment of the catalytic domains of human eEF-2 kinase, C. elegans eEF-2 kinase, MHCK A and B, MhkC and the mammalian eEF-2-kinase-related proteins is shown in Figure 1. Altogether there are 20 positions in the alignment that are identical in all eight proteins, and there are 57 amino acids that are identical in at least six out of the eight proteins. Eight subdomains (I–VIII) can be identified; there is no significant homology between these eight subdomains and any of the twelve subdomains of the conventional protein kinases. Subdomain VI contains a typical Walker type B motif, which consists of four hydrophobic amino acids followed by an aspartate residue [[8]Walker JE Saraste M Runswick MJ Gay NJ Distantly related sequences in the alpha- and beta-subunits of ATP synthase, myosin, kinases and other ATP-requiring enzymes and a common nucleotide binding fold.EMBO J. 1982; 1: 945-951Crossref PubMed Scopus (4131) Google Scholar]. This motif is present in various proteins catalyzing ATP-triggered reactions and is involved in the coordination of Mg2+ bound to the phosphates of ATP [[9]Yoshida M Amano T A common topology of proteins catalyzing ATP-triggered reactions.FEBS Lett. 1995; 359: 1-5Abstract Full Text PDF PubMed Scopus (91) Google Scholar]. In addition, subdomain VIII contains a glycine-rich motif that is typical of ATP-binding sites in the catalytic domain of conventional protein kinases, although in those protein kinases it is located at the extreme amino terminus of the catalytic domain. Why does Nature use such unusual kinases to phosphorylate eEF-2 and myosin heavy chains? We suggest that the explanation may be found in their mechanism of substrate recognition. It is well-known that the substrate specificity of both serine/threonine and tyrosine protein kinases is determined predominantly by the primary structure around the phosphorylation site rather than by secondary or tertiary structure. As was originally reported by Small, Chou and Fasman [[10]Small D Chou PY Fasman GD Occurrence of phosphorylated residues in predicted β-turns: implication for β-turn participation in control mechanisms.Biochem Biophys Res Commun. 1977; 79: 341-346Crossref PubMed Scopus (70) Google Scholar], phosphorylation sites in proteins often occur in predicted β turns. Subsequent studies, including X-ray structure data, demonstrated that phosphoacceptor sites for conventional protein kinases are usually located in turns, loops or irregular regions that have a flexible conformation (reviewed in [[11]Pinna LA Ruzzene M How do protein kinases recognize their substrates?.Biochim Biophys Acta. 1996; 1314: 191-225Crossref PubMed Scopus (389) Google Scholar]). Recently, it was shown both for an insulin receptor tyrosine kinase and for phosphorylase kinase that binding of the active site to the substrate involves the formation of a short antiparallel β sheet between the substrate and the activation loop of the kinase [12Hubbard SR Crystal structure of the activated insulin receptor tyrosine kinase in complex with peptide substrate and ATP analog.EMBO J. 1997; 16: 5572-5581Crossref PubMed Scopus (747) Google Scholar, 13Lowe ED Noble MEM Skamnaki VT Oikonomakos NG Owen DJ Johnson LN The crystal structure of a phosphorylase kinase peptide substrate complex: kinase substrate recognition.EMBO J. 1997; 16: 6646-6658Crossref PubMed Scopus (170) Google Scholar]. It is likely that the irregular, flexible structure of the substrates of conventional protein kinases may be necessary for formation of the β sheet at the active site. In contrast to this, existing evidence suggests that the peptides around the phosphorylation sites in eEF-2 and Dictyostelium myosin II heavy chains have an α-helical conformation. The two MHCK A phosphorylation sites are located in a coiled-coil α-helical region of myosin heavy chains [[14]Vaillancourt JP Lyons C Côté GP Identification of two phosphorylated threonines in the tail region of Dictyostelium myosin II.J Biol Chem. 1988; 263: 10082-10087Abstract Full Text PDF PubMed Google Scholar]. Sequences surrounding the two MHCK A phosphorylation sites are very different; in both cases, however, the phosphoacceptor threonine residues are located in the same position in the heptad repeat of the coiled-coil [[14]Vaillancourt JP Lyons C Côté GP Identification of two phosphorylated threonines in the tail region of Dictyostelium myosin II.J Biol Chem. 1988; 263: 10082-10087Abstract Full Text PDF PubMed Google Scholar], suggesting that secondary structure rather than primary structure is the determinant for this protein kinase. The major phosphorylation site in eEF-2 (Thr56) is located within a sequence that is homologous among all elongation factors. It can be seen from the crystal structure of EF-Tu that this site has an α-helical conformation [15Abel K Yoder MD Hilgenfeld R Jurnak F An α to β conformational switch in EF-Tu.Structure. 1996; 4: 1153-1159Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar, 16Polekhina G Thirup S Kjeldgaard M Nissen P Lippmann C Nyborg J Helix unwinding in the effector region of elongation factor EF-Tu-GDP.Structure. 1996; 4: 1141-1151Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar]. These findings suggest an explanation for why eEF-2 kinase and MHCK A are so different from the conventional protein kinases: their catalytic domain may be adapted to recognize and phosphorylate amino acids located within α helices. We suggest, therefore, that this new class of protein kinases be named ‘alpha-kinases’ (α-kinases). Intriguingly, both eEF-2 kinase and MHCK A phosphorylate their substrates exclusively on threonine residues. It was recently shown that phosphothreonine, but not phosphoserine, can destabilize α helices [[17]Szilak L Moitra J Krylov D Vinson C Phosphorylation destabilizes α-helices.Nat Struct Biol. 1997; 4: 112-114Crossref PubMed Scopus (75) Google Scholar]. Phosphorylation of α helices on threonine residues could therefore lead to a drastic alteration in protein structure affecting the function of the substrate proteins. No matter what mechanism they use for substrate recognition, α-kinases clearly have a new type of kinase catalytic domain, characterized by a unique set of motifs. Previously, two types of protein kinase catalytic domains were known and characterized: the catalytic domain of eukaryotic serine/threonine/tyrosine protein kinases, and the catalytic domain of histidine protein kinases of bacterial two-component regulators. The three-dimensional structure of a bacterial histidine kinase has been determined recently and was found to be completely different from the conventional eukaryotic protein kinases [[18]Tanaka T Saha SK Tomomori C Ishima R Liu D Tong KI et al.NMR structure of the histidine kinase domain of the E. coli osmosensor EnvZ.Nature. 1998; 396: 88-92Crossref PubMed Scopus (215) Google Scholar]. It is interesting that the glycine-rich motif in histidine kinases is located close to the carboxyl terminus of the catalytic domain, which is similar to the location of the glycine-rich motif in α-kinases. Further studies are required to find out whether this is purely a coincidence, or whether α-kinases and histidine kinases are evolutionarily related. AG Ryazanov, KS Pavur and MV Dorovkov, Department of Pharmacology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, New Jersey 08854, USA. E-mail address for AG Ryazanov: [email protected]" @default.
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• W1993990713 title "Alpha-kinases: a new class of protein kinases with a novel catalytic domain" @default.
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