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Emerging roles of the αC‐β4 loop in protein kinase structure, function, evolution, and disease
Author(s) -
Yeung Wayland,
Ruan Zheng,
Kannan Natarajan
Publication year - 2020
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.2253
Subject(s) - kinome , allosteric regulation , protein kinase domain , kinase , biology , protein structure , computational biology , protein kinase a , microbiology and biotechnology , c raf , scaffold protein , genetics , biochemistry , cyclin dependent kinase 2 , signal transduction , gene , enzyme , mutant
The faithful propagation of cellular signals in most organisms relies on the coordinated functions of a large family of protein kinases that share a conserved catalytic domain. The catalytic domain is a dynamic scaffold that undergoes large conformational changes upon activation. Most of these conformational changes, such as movement of the regulatory αC‐helix from an “out” to “in” conformation, hinge on a conserved, but understudied, loop termed the αC‐β4 loop, which mediates conserved interactions to tether flexible structural elements to the kinase core. We previously showed that the αC‐β4 loop is a unique feature of eukaryotic protein kinases. Here, we review the emerging roles of this loop in kinase structure, function, regulation, and diseases. Through a kinome‐wide analysis, we define the boundaries of the loop for the first time and show that sequence and structural variation in the loop correlate with conformational and regulatory variation. Many recurrent disease mutations map to the αC‐β4 loop and contribute to drug resistance and abnormal kinase activation by relieving key auto‐inhibitory interactions associated with αC‐helix and inter‐lobe movement. The αC‐β4 loop is a hotspot for post‐translational modifications, protein–protein interaction, and Hsp90 mediated folding. Our kinome‐wide analysis provides insights for hypothesis‐driven characterization of understudied kinases and the development of allosteric protein kinase inhibitors.