Apr 14, 2020

Specific PIP2 Binding Promotes Calcium Activation of TMEM16A Chloride Channels

BioRxiv : the Preprint Server for Biology
Jia, Jianhan Chen

Abstract

TMEM16A is a widely expressed Ca2+-activated Cl- channel that regulates important 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 determined with saturating Ca2+ have failed to reveal an activated state with unobstructed permeation pathway. This has been attributed to the requirement of PIP2 for preventing TMEM16A desensitization. Here, we show that specific binding PIP2 to TMEM16A can lead to spontaneous opening of the permeation pathway in the Ca2+-bound state. The predicted activated state is highly consistent with a wide range of mutagenesis and functional data. It yields a maximal Cl- conductance of ~1 pS, similar to experimental estimates, and recapitulates the selectivity of larger SCN- over Cl-. The resulting molecular mechanism of activation provides a basis for understanding the interplay of multiple signals in controlling TMEM16A channel function.

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Mentioned in this Paper

Zone
Genome
No Data re: Ingredient
Nucleic Acid Hybridization Procedure
Isolation Aspects
Environment
House mice
Adaptation
Structure
Molpadia musculus

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