title: Dimerization-induced allostery in protein kinase regulation.
abstract: 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 αC is a key hub on which regulatory inputs converge to induce catalytic switching. An emerging mechanism involved in regulating helix αC 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 eIF2α 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.
authors.affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Québec, H3C 3J7, Canada.
authors.forename: Hugo
authors.initials: H
authors.lastname: Lavoie
authors.affiliation: The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, M5S 1A8, Canada.
authors.forename: John J
authors.initials: JJ
authors.lastname: Li
authors.affiliation: The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, M5G 1X5, Canada; Department of Biochemistry, University of Toronto, Toronto, Ontario, M5S 1A8, Canada.
authors.forename: Neroshan
authors.initials: N
authors.lastname: Thevakumaran
authors.affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Québec, H3C 3J7, Canada; Département de Pathologie et Biologie Cellulaire, Université de Montréal, Montréal, Québec, H3C 3J7, Canada. Electronic address: marc.therrien@umontreal.ca.
authors.forename: Marc
authors.initials: M
authors.lastname: Therrien
authors.affiliation: The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, M5S 1A8, Canada; Department of Biochemistry, University of Toronto, Toronto, Ontario, M5S 1A8, Canada. Electronic address: sicheri@lunenfeld.ca.
authors.forename: Frank
authors.initials: F
authors.lastname: Sicheri
mesh_terms: D000494:Allosteric Regulation; D004722:Endoribonucleases / Q000378:metabolism; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008958:Models, Molecular; D010766:Phosphorylation; D011487:Protein Conformation; D011494:Protein Kinases / Q000378:metabolism*; D055503:Protein Multimerization; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary / Q000502:physiology; D015398:Signal Transduction; D048490:raf Kinases / Q000378:metabolism
chemical_list: D011494:Protein Kinases; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; C531557:eIF2alpha kinase, mouse; D048490:raf Kinases; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease
keywords: allosteric regulation; dimerization; protein kinases; pseudokinase