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Evolution of a dynamic molecular switch
Author(s) -
Taylor Susan S.,
Meharena Hiruy S.,
Kornev Alexandr P.
Publication year - 2019
Publication title -
iubmb life
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.132
H-Index - 113
eISSN - 1521-6551
pISSN - 1521-6543
DOI - 10.1002/iub.2059
Subject(s) - kinase , protein kinase a , conserved sequence , biology , computational biology , microbiology and biotechnology , biochemistry , gene , peptide sequence
Eukaryotic protein kinases (EPKs) regulate almost every biological process and have evolved to be dynamic molecular switches; this is in stark contrast to metabolic enzymes, which have evolved to be efficient catalysts. In particular, the highly conserved active site of every EPK is dynamically and transiently assembled by a process that is highly regulated and unique for every protein kinase. We review here the essential features of the kinase core, focusing on the conserved motifs and residues that are embedded in every kinase. We explore, in particular, how the hydrophobic core architecture specifically drives the dynamic assembly of the regulatory spine and consequently the organization of the active site where the γ‐phosphate of ATP is positioned by a convergence of conserved motifs including a conserved regulatory triad for transfer to a protein substrate. In conclusion, we show how the flanking N‐ and C‐terminal tails often classified as intrinsically disordered regions, as well as flanking domains, contribute in a highly kinase‐specific manner to the regulation of the conserved kinase core. Understanding this process as well as how one kinase activates another remains as two of the big challenges for the kinase signaling community. © 2019 IUBMB Life, 71(6):672–684, 2019