Recognition of sites of functional specialisation in all known eukaryotic protein kinase families

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.

Evolution of protein kinase substrate recognition at the active site

“…The analysis here of divergent residues across kinase families follows a similar analysis employing a BLAST-based approach [59]. This study is focused on the kinase catalytic domain, and we did not take into account the evolution of kinase domain composition or sequence changes outside the catalytic domain, which may have a significant impact on catalytic function [60].…”

Evolution of protein kinase substrate recognition at the active site

“…The analysis here of divergent residues across kinase families follows a similar analysis employing a BLAST-based approach (Kalaivani, Reema, and Srinivasan 2018). This analysis is focused here on the kinase catalytic domain and we did not take into account the evolution of domain composition or sequence changes outside the catalytic domain, which may have a significant impact on catalytic function (Pearce, Komander, and Alessi 2010).…”

Specialized structural and functional roles of residues selectively conserved in subfamilies of the pleckstrin homology domain family

“…In addition to Ins (1,3,4,5) P4, it can also bind to another phosphoinositide Ins (1,4,5) P3. The terminologies used in PDB for Ins (1,3,4,5) P4 and Ins (1,4,5) P3 are 4IP and I3P, respectively. There are nine DA-specific residues involved in interaction with Ins (1,3,4,5) P4 in 2G variant and seven DA-specific residues from 3G variant to interact with Ins (1,4,5) P3.…”

“…Homologous proteins are known to perform same or similar functions, but their functional levels, specificity to ligands, and regulatory mechanisms may vary among homologues . These differences between homologues are known to be achieved by their sequence differences and the kinds of domains to which the domain of interest is tethered in multidomain proteins .…”