Please use this identifier to cite or link to this item: https://doi.org/10.1098/rstb.2012.0010
Title: Protein kinases display minimal interpositional dependence on substrate sequence: Potential implications for the evolution of signalling networks
Authors: Joughin, B.A.
Liu, C.
Lauffenburger, D.A.
Hogue, C.W.V. 
Yaffe, M.B.
Keywords: Kinase substrate specificity
Phosphorylation
Signalling networks
Issue Date: 19-Sep-2012
Citation: Joughin, B.A., Liu, C., Lauffenburger, D.A., Hogue, C.W.V., Yaffe, M.B. (2012-09-19). Protein kinases display minimal interpositional dependence on substrate sequence: Potential implications for the evolution of signalling networks. Philosophical Transactions of the Royal Society B: Biological Sciences 367 (1602) : 2574-2583. ScholarBank@NUS Repository. https://doi.org/10.1098/rstb.2012.0010
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. © 2012 The Royal Society.
Source Title: Philosophical Transactions of the Royal Society B: Biological Sciences
URI: http://scholarbank.nus.edu.sg/handle/10635/101478
ISSN: 09628436
DOI: 10.1098/rstb.2012.0010
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