Cancer-associated arginine-to-histidine mutations confer a gain in pH sensing to mutant proteins.

ABSTRACT: The intracellular pH (pHi) of most cancers is constitutively higher than that of normal cells and enhances proliferation and cell survival. We found that increased pHi enabled the tumorigenic behaviors caused by somatic arginine-to-histidine mutations, which are frequent in cancer and confer pH sensing not seen with wild-type proteins. Experimentally raising the pHi increased the activity of R776H mutant epidermal growth factor receptor (EGFR-R776H), thereby increasing proliferation and causing transformation in fibroblasts. An Arg-to-Gly mutation did not confer these effects. Molecular dynamics simulations of EGFR suggested that decreased protonation of His⁷⁷⁶ at high pH causes conformational changes in the αC helix that may stabilize the active form of the kinase. An Arg-to-Hi

SUBMITTER: White KA 

PROVIDER: S-EPMC6022362 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature