期刊名称:Proceedings of the National Academy of Sciences
印刷版ISSN:0027-8424
电子版ISSN:1091-6490
出版年度:2003
卷号:100
期号:8
页码:4463-4468
DOI:10.1073/pnas.0737647100
语种:English
出版社:The National Academy of Sciences of the United States of America
摘要:The binding between a PK and its target is highly specific, despite the fact that many different PKs exhibit significant sequence and structure homology. There must be, then, specificity-determining residues (SDRs) that enable different PKs to recognize their unique substrate. Here we use and further develop a computational procedure to discover putative SDRs (PSDRs) in protein families, whereby a family of homologous proteins is split into orthologous proteins, which are assumed to have the same specificity, and paralogous proteins, which have different specificities. We reason that PSDRs must be similar among orthologs, whereas they must necessarily be different among paralogs. Our statistical procedure and evolutionary model identifies such residues by discriminating a functional signal from a phylogenetic one. As case studies we investigate the prokaryotic two-component system and the eukaryotic AGC (i.e., cAMP-dependent PK, cGMP-dependent PK, and PKC) PKs. Without using experimental data, we predict PSDRs in prokaryotic and eukaryotic PKs, and suggest precise mutations that may convert the specificity of one PK to another. We compare our predictions with current experimental results and obtain considerable agreement with them. Our analysis unifies much of existing data on PK specificity. Finally, we find PSDRs that are outside the active site. Based on our results, as well as structural and biochemical characterizations of eukaryotic PKs, we propose the testable hypothesis of "specificity via differential activation" as a way for the cell to control kinase specificity.