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An Additional Ca²⁺ Binding Site Allosterically Controls TMEM16A Activation.

Son C Le¹, Huanghe Yang²

¹Department of Biochemistry, Duke University School of Medicine, Durham, NC 27710, USA.

|December 30, 2020

Summary

This summary is machine-generated.

Calcium (Ca2+) activates TMEM16 channels and scramblases. This study confirms a third Ca2+ binding site in TMEM16A, enhancing channel function and revealing a long-range allosteric gating mechanism.

Keywords:

Ca(2+) binding sites Ca(2+)-activated chloride channels CaCC TMEM16 allosteric modulation channel activation and inhibition channel gating phospholipid scramblases transmembrane protein 16

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Area of Science:

Molecular and Cellular Biology
Biophysics
Physiology

Background:

Transmembrane protein 16 (TMEM16) proteins function as Ca2+-activated chloride channels and phospholipid scramblases.
These proteins regulate vital physiological processes including muscle contraction, blood coagulation, and tumor growth.
While two orthosteric Ca2+ binding sites are known to activate TMEM16 channels, the function of a third potential site remains unclear.

Purpose of the Study:

To investigate the functional relevance of a third Ca2+ binding site in TMEM16A.
To elucidate the role of this site in channel activation and gating.

Main Methods:

Utilized cadmium (Cd2+) metal bridging experiments.
Analyzed Ca2+ binding affinity and its effect on TMEM16A channel activity.

Main Results:

Confirmed high-affinity Ca2+ binding to a third site in TMEM16A.
Demonstrated that this third Ca2+ site significantly enhances channel activation.
Showed that conformational states of the third site profoundly influence TMEM16A opening.

Conclusions:

Established the existence and functional importance of a third Ca2+ binding site in TMEM16A.
Provided insights into a long-range allosteric gating mechanism for TMEM16 channels and scramblases.