Abstract
The conserved function of protein phosphorylation, catalysed by members of protein kinase superfamily, is regulated in different ways in different kinase families. Further, differences in activating triggers, cellular localisation, domain architecture and substrate specificity between kinase families are also well known. While the transfer of γ-phosphate from ATP to the hydroxyl group of Ser/Thr/Tyr is mediated by a conserved Asp, the characteristic functional and regulatory sites are specialized at the level of families or sub-families. Such family-specific sites of functional specialization are unknown for most families of kinases. In this work, we systematically identify the family-specific residue features by comparing the extent of conservation of physicochemical properties, Shannon entropy and statistical probability of residue distributions between families of kinases. An integrated discriminatory score, which combines these three features, is developed to demarcate the functionally specialized sites in a kinase family from other sites. We achieved an area under ROC curve of 0.992 for the discrimination of kinase families. Our approach was extensively tested on well-studied families CDK and MAPK, wherein specific protein interaction sites and substrate recognition sites were successfully detected (p-value < 0.05). We also find that the known family-specific oncogenic driver mutation sites were scored high by our method. The method was applied to all known kinases encompassing 107 families from diverse eukaryotic organisms leading to a comprehensive list of family-specific functional sites. Apart from other uses, our method facilitates identification of specific protein interaction sites and drug target sites in a kinase family.
Highlights
Protein kinases, as key regulators of cellular functions, are among the largest and most diverse protein superfamilies known [1,2]
Protein kinases are molecular switches that destine crucial decision points in cell signalling pathways. They are implicated in the normal functioning of a cell as well as in various cancers if mutated
The results of the study are organised into four major sections: (i) dataset curation, explaining the method of selection and organisation of STY kinase catalytic domain sequences, (ii) method development, detailing the rationale and protocol to identify differentially conserved sites in kinases and maximise the discriminability among them, (iii) method assessment and validation, elucidating its performance by application to known sites of functional specialisation in a few well studied kinases, and (iv) application, demonstrating a feasible avenue for practical use of the method and applying it to all known kinases
Summary
As key regulators of cellular functions, are among the largest and most diverse protein superfamilies known [1,2] On account of their phosphotransfer function to a Ser / Thr / Tyr residue in eukaryotes, they are known as STY kinases. Kinases exhibit high diversity in terms of differences in activating triggers [5,6,7,8], regulatory mechanisms [9,10], cellular localisation [11,12,13], domain architectures [1] and substrate specificity [14] In this context of dualism of similarity and differences, the modules responsible for common and preserved features, like, ATP binding [15], phosphotransfer [16] and 3-dimensional conformation of active state [17] are well known. For many kinases the sites of functional specialization is yet unknown
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