The repertoire of protein kinases encoded in the draft version of the human genome: atypical variations and uncommon domain combinations.
BACKGROUND
Phosphorylation by protein kinases is central to cellular signal transduction. Abnormal functioning of kinases has been implicated in developmental disorders and malignancies. Their activity is regulated by second messengers and by the binding of associated domains, which are also influential in translocating the catalytic component to their substrate sites, in mediating interaction with other proteins and carrying out their biological roles.


RESULTS
Using sensitive profile-search methods and manual analysis, the human genome has been surveyed for protein kinases. A set of 448 sequences, which show significant similarity to protein kinases and contain the critical residues essential for kinase function, have been selected for an analysis of domain combinations after classifying the kinase domains into subfamilies. The unusual domain combinations in particular kinases suggest their involvement in ubiquitination pathways and alternative modes of regulation for mitogen-activated protein kinase kinases (MAPKKs) and cyclin-dependent kinase (CDK)-like kinases. Previously unexplored kinases have been implicated in osteoblast differentiation and embryonic development on the basis of homology with kinases of known functions from other organisms. Kinases potentially unique to vertebrates are involved in highly evolved processes such as apoptosis, protein translation and tyrosine kinase signaling. In addition to coevolution with the kinase domain, duplication and recruitment of non-catalytic domains is apparent in signaling domains such as the PH, DAG-PE, SH2 and SH3 domains.


CONCLUSIONS
Expansion of the functional repertoire and possible existence of alternative modes of regulation of certain kinases is suggested by their uncommon domain combinations. Experimental verification of the predicted implications of these kinases could enhance our understanding of their biological roles.
Krupa
A
A
Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560 012, India.
Srinivasan
N
N
D020816:Amino Acid Motifs / Q000235:genetics; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics; D017173:Caenorhabditis elegans / Q000201:enzymology / Q000235:genetics; D020134:Catalytic Domain / Q000235:genetics; D030541:Databases, Genetic; D004331:Drosophila melanogaster / Q000201:enzymology / Q000235:genetics; D014644:Genetic Variation; D016678:Genome; D015894:Genome, Human; D006801:Humans; D051379:Mice; D011494:Protein Kinases / Q000235:genetics*; D017434:Protein Structure, Tertiary / Q000235:genetics; D012689:Sequence Homology, Nucleic Acid; D013379:Substrate Specificity / Q000235:genetics; D018909:src Homology Domains / Q000235:genetics
D001426:Bacterial Proteins; D011494:Protein Kinases