Specific PIP₂ binding promotes calcium activation of TMEM16A chloride channels.

ABSTRACT: TMEM16A is a widely expressed Ca²⁺-activated Cl^- channel that regulates crucial physiological functions including fluid secretion, neuronal excitability, and smooth muscle contraction. There is a critical need to understand the molecular mechanisms of TMEM16A gating and regulation. However, high-resolution TMEM16A structures have failed to reveal an activated state with an unobstructed permeation pathway even with saturating Ca²⁺. This has been attributed to the requirement of PIP₂ for preventing TMEM16A desensitization. Here, atomistic simulations show that specific binding of PIP₂ to TMEM16A can lead to spontaneous opening of the permeation pathway in the Ca²⁺-bound state. The predicted activated state is highly consistent

SUBMITTER: Jia Z 

PROVIDER: S-EPMC7910439 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature