An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor.
The mechanism by which the epidermal growth factor receptor (EGFR) is activated upon dimerization has eluded definition. We find that the EGFR kinase domain can be activated by increasing its local concentration or by mutating a leucine (L834R) in the activation loop, the phosphorylation of which is not required for activation. This suggests that the kinase domain is intrinsically autoinhibited, and an intermolecular interaction promotes its activation. Using further mutational analysis and crystallography we demonstrate that the autoinhibited conformation of the EGFR kinase domain resembles that of Src and cyclin-dependent kinases (CDKs). EGFR activation results from the formation of an asymmetric dimer in which the C-terminal lobe of one kinase domain plays a role analogous to that of cyclin in activated CDK/cyclin complexes. The CDK/cyclin-like complex formed by two kinase domains thus explains the activation of EGFR-family receptors by homo- or heterodimerization.
Zhang
Xuewu
X
Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, 94720, USA.
Gureasko
Jodi
J
Shen
Kui
K
Cole
Philip A
PA
Kuriyan
John
J
D000494:Allosteric Regulation; D000595:Amino Acid Sequence; D000818:Animals; D018360:Crystallography, X-Ray; D018844:Cyclin-Dependent Kinases / Q000737:chemistry; D019281:Dimerization; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007930:Leucine / Q000235:genetics; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D019061:src-Family Kinases / Q000737:chemistry
D066246:ErbB Receptors; D019061:src-Family Kinases; D018844:Cyclin-Dependent Kinases; D007930:Leucine