Identification of conserved structural motifs associated with phosphorylation sites in kinases
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Background: Protein phosphorylation plays a crucial role in the regulation of several cellular processes. Protein kinases are enzymes that catalyze the event of phosphorylation and are themselves regulated by phosphorylation. Regulation by phosphorylation involves formation of a key structural motif within kinases called the RD-pocket. The canonical RD-pocket is formed by three basic residues projecting from different regions of the kinase. Although the importance of the motif has been appreciated in some kinase families, whether or not this is a general feature of other kinases is not well understood. Also, recurrence of the motif in other regions of the kinase for regulation has not been well explored. With the goal of using the structural motif as a feature for predicting allosteric sites we performed a detailed analysis of the RD-pocket in kinases. Results: Using structural bioinformatics tools we performed a detailed analysis of the canonical RD-pocket in a library of 1924 kinase structures. We found that apart from the canonical RD-pocket which is well known to be associated with regulation, several alternate RD-pockets exist. Study of the alternate RD-pockets suggests that the altered location of the RD-pockets have presumably emerged to meet the specific requirements of every kinase family. In addition to the RD-pockets, several other pockets called the “non-RD” pockets are in found in other regions of the kinase domain. In a library of 1924 kinase structures, 35 canonical RD-pockets, 39 alternate RD-pockets and 57 non-RD pockets are identified with RMSD of 1 Å from canonical RD-pocket in CDK. Detailed analysis of non-RD pockets in kinase families such as SRC, CDK2, MAPK8, VRK2 and CHK1 provided important clues regarding the functional role of the pockets. Specifically in MAPK8, we found the non-RD pocket is associated with the C-terminal tail tyrosine (Y357). Potential phosphorylation of the tyrosine can lead to conformational changes in the kinase domain, thereby leading to regulation or activation. Conclusion: The analysis suggests that the basic pocket is a characteristic phospho-acceptor site in kinases whose main function is to allosterically couple the phosphorylation site to distal active and regulatory sites. The recurrent pocket is an important structural feature that can be used in the prediction of potential allosteric sites regulated by phosphorylation in kinases.