title: Co-conserved MAPK features couple D-domain docking groove to distal allosteric sites via the C-terminal flanking tail.
abstract: Mitogen activated protein kinases (MAPKs) form a closely related family of kinases that control critical pathways associated with cell growth and survival. Although MAPKs have been extensively characterized at the biochemical, cellular, and structural level, an integrated evolutionary understanding of how MAPKs differ from other closely related protein kinases is currently lacking. Here, we perform statistical sequence comparisons of MAPKs and related protein kinases to identify sequence and structural features associated with MAPK functional divergence. We show, for the first time, that virtually all MAPK-distinguishing sequence features, including an unappreciated short insert segment in the β4-β5 loop, physically couple distal functional sites in the kinase domain to the D-domain peptide docking groove via the C-terminal flanking tail (C-tail). The coupling mediated by MAPK-specific residues confers an allosteric regulatory mechanism unique to MAPKs. In particular, the regulatory αC-helix conformation is controlled by a MAPK-conserved salt bridge interaction between an arginine in the αC-helix and an acidic residue in the C-tail. The salt-bridge interaction is modulated in unique ways in individual sub-families to achieve regulatory specificity. Our study is consistent with a model in which the C-tail co-evolved with the D-domain docking site to allosterically control MAPK activity. Our study provides testable mechanistic hypotheses for biochemical characterization of MAPK-conserved residues and new avenues for the design of allosteric MAPK inhibitors.
authors: Department of Biochemistry & Molecular Biology, University of Georgia, Athens, Georgia, United States of America.
authors: Tuan
authors: T
authors: Nguyen
authors: Institute of Bioinformatics, University of Georgia, Athens, Georgia, United States of America.
authors: Zheng
authors: Z
authors: Ruan
authors: Department of Biochemistry & Molecular Biology, University of Georgia, Athens, Georgia, United States of America.
authors: Krishnadev
authors: K
authors: Oruganty
authors: Department of Biochemistry & Molecular Biology, University of Georgia, Athens, Georgia, United States of America; Institute of Bioinformatics, University of Georgia, Athens, Georgia, United States of America.
authors: Natarajan
authors: N
authors: Kannan
mesh_terms: D000495:Allosteric Site; D000595:Amino Acid Sequence; D001665:Binding Sites; D020134:Catalytic Domain; D019295:Computational Biology; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity
chemical_list: D020928:Mitogen-Activated Protein Kinases