Title | Protein kinases display minimal interpositional dependence on substrate sequence: potential implications for the evolution of signalling networks. |
Publication Type | Journal Article |
Year of Publication | 2012 |
Authors | Joughin, BA, Liu, C, Lauffenburger, DA, Hogue, CWV, Yaffe, MB |
Journal | Philos Trans R Soc Lond B Biol Sci |
Volume | 367 |
Issue | 1602 |
Pagination | 2574-83 |
Date Published | 2012 Sep 19 |
ISSN | 1471-2970 |
Keywords | Amino Acid Motifs, Amino Acid Sequence, Binding Sites, CDC2 Protein Kinase, Cell Cycle Proteins, Evolution, Molecular, Humans, Models, Molecular, Phosphopeptides, Phosphorylation, Protein Conformation, Protein Interaction Mapping, Protein-Serine-Threonine Kinases, Signal Transduction, Substrate Specificity |
Abstract | Characterization of in vitro substrates of protein kinases by peptide library screening provides a wealth of information on the substrate specificity of kinases for amino acids at particular positions relative to the site of phosphorylation, but provides no information concerning interdependence among positions. High-throughput techniques have recently made it feasible to identify large numbers of in vivo kinase substrates. We used data from experiments on the kinases ATM/ATR and CDK1, and curated CK2 substrates to evaluate the prevalence of interactions between substrate positions within a motif and the utility of these interactions in predicting kinase substrates. Among these data, evidence of interpositional sequence dependencies is strikingly rare, and what dependency exists does little to aid in the prediction of novel kinase substrates. Significant increases in the ability of models to predict kinase-substrate specificity beyond position-independent models must come largely from inclusion of elements of biological and cellular context, rather than further analysis of substrate sequences alone. Our results suggest that, evolutionarily, kinase substrate fitness exists in a smooth energetic landscape. Taken with results from others indicating that phosphopeptide-binding domains do exhibit interpositional dependence, our data suggest that incorporation of new substrate molecules into phospho-signalling networks may be rate-limited by the evolution of suitability for binding by phosphopeptide-binding domains. |
DOI | 10.1098/rstb.2012.0010 |
Alternate Journal | Philos. Trans. R. Soc. Lond., B, Biol. Sci. |
PubMed ID | 22889908 |
PubMed Central ID | PMC3415838 |
Grant List | CA112967 / CA / NCI NIH HHS / United States ES015339 / ES / NIEHS NIH HHS / United States R24-DK090963 / DK / NIDDK NIH HHS / United States |