Structure

Abstract

An autoinhibitory network of hydrogen bonds located at the kinase hinge (referred to as the "molecular brake") regulates the activity of several receptor tyrosine kinases. The mechanism whereby mutational disengagement of the brake allosterically activates the kinase in human disease is incompletely understood. We used a combination of NMR, bioinformatics, and molecular dynamics simulation to show that mutational disruption of the molecular brake triggers localized conformational perturbations that propagate to the active site. This entails changes in interactions of an isoleucine, one of three hydrophobic residues that lock the phenylalanine of the DFG motif in an inactive conformation. Structural analysis of tyrosine kinases provides evidence that this allosteric control mechanism is shared across the tyrosine kinase family. We also show that highly activating mutations at the brake diminish the enzyme's thermostability, thereby explaining why these mutations cause milder skeletal syndromes compared with less-activating mutations in the activation loop.R01 GM117118/GM/NIGMS NIH HHS/United StatesS10 OD016343/CD/ODCDC CDC HHS/United StatesR01 DE013686/DE/NIDCR NIH HHS/United StatesR01 GM117118/GM/NIGMS NIH HHS/United StatesR35 GM127040/GM/NIGMS NIH HHS/United StatesR01 DE013686/DE/NIDCR NIH HHS/United StatesF99 CA212474/CA/NCI NIH HHS/United StatesS10 OD016343/OD/NIH HHS/United States2020-08-06T00:00:00Z31204250PMC66875256564vault:3370