Activation of TMEM16F by inner gate charged mutations and possible lipid/ion permeation mechanisms.

ABSTRACT: Transmembrane protein 16F (TMEM16F) is a ubiquitously expressed Ca²⁺-activated phospholipid scramblase that also functions as a largely non-selective ion channel. Though recent structural studies have revealed the closed and intermediate conformations of mammalian TMEM16F (mTMEM16F), the open and conductive state remains elusive. Instead, it has been proposed that an open hydrophilic pathway may not be required for lipid scrambling. We previously identified an inner activation gate, consisting of F518, Y563, and I612, and showed that charged mutations of the inner gate residues led to constitutively active mTMEM16F scrambling. Herein, atomistic simulations show that lysine substitution of F518 and Y563 can indeed lead to spontaneous opening of the permeation pore in the Ca²

SUBMITTER: Jia Z 

PROVIDER: S-EPMC9515230 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature