期刊
TRENDS IN BIOCHEMICAL SCIENCES
卷 39, 期 10, 页码 475-486出版社
ELSEVIER SCIENCE LONDON
DOI: 10.1016/j.tibs.2014.08.004
关键词
dimerization; allosteric regulation; protein kinases; pseudokinase
The ability of protein kinases to switch between inactive and active states is critical to control the outputs of cellular signaling pathways. In several protein kinases, the conformation of helix alpha C is a key hub on which regulatory inputs converge to induce catalytic switching. An emerging mechanism involved in regulating helix alpha C orientation is the allosteric coupling with kinase domain surfaces involved in homo- or heterodimerization. In this review, we discuss dimerization-mediated regulation of the rapidly accelerated fibrosarcoma (RAF) and elF2 alpha kinase families and draw parallels with the analogous behavior of the epidermal growth factor receptor (EGFR) and serine/threonine-protein kinase endoribonuclease 1 (IRE1)/ribonuclease L (RNAse L) kinase families. Given that resistance to RAF-targeted therapeutics often stems from dimerization-dependent mechanisms, we suggest that a better understanding of dimerization-induced allostery may assist in developing alternate therapeutic strategies.
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