An Additional Ca²⁺ Binding Site Allosterically Controls TMEM16A Activation.

ABSTRACT: Calcium (Ca²⁺) is the primary stimulus for transmembrane protein 16 (TMEM16) Ca²⁺-activated chloride channels and phospholipid scramblases, which regulate important physiological processes ranging from smooth muscle contraction to blood coagulation and tumor progression. Binding of intracellular Ca²⁺ to two highly conserved orthosteric binding sites in transmembrane helices (TMs) 6-8 efficiently opens the permeation pathway formed by TMs 3-7. Recent structures of TMEM16K and TMEM16F scramblases revealed an additional Ca²⁺ binding site between TM2 and TM10, whose functional relevance remains unknown. Here, we report that Ca²⁺ binds with high affinity to the equivalent third Ca²⁺ site in TMEM16A to enhance channel activation.

SUBMITTER: Le SC 

PROVIDER: S-EPMC7786149 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature