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Molecular underpinning of intracellular pH regulation on TMEM16F.

Publication ,  Journal Article
Liang, P; Yang, H
Published in: J Gen Physiol
February 1, 2021

TMEM16F, a dual-function phospholipid scramblase and ion channel, is important in blood coagulation, skeleton development, HIV infection, and cell fusion. Despite advances in understanding its structure and activation mechanism, how TMEM16F is regulated by intracellular factors remains largely elusive. Here we report that TMEM16F lipid scrambling and ion channel activities are strongly influenced by intracellular pH (pHi). We found that low pHi attenuates, whereas high pHi potentiates, TMEM16F channel and scramblase activation under physiological concentrations of intracellular Ca2+ ([Ca2+]i). We further demonstrate that TMEM16F pHi sensitivity depends on [Ca2+]i and exhibits a bell-shaped relationship with [Ca2+]i: TMEM16F channel activation becomes increasingly pHi sensitive from resting [Ca2+]i to micromolar [Ca2+]i, but when [Ca2+]i increases beyond 15 µM, pHi sensitivity gradually diminishes. The mutation of a Ca2+-binding residue that markedly reduces TMEM16F Ca2+ sensitivity (E667Q) maintains the bell-shaped relationship between pHi sensitivity and Ca2+ but causes a dramatic shift of the peak [Ca2+]i from 15 µM to 3 mM. Our biophysical characterizations thus pinpoint that the pHi regulatory effects on TMEM16F stem from the competition between Ca2+ and protons for the primary Ca2+-binding residues in the pore. Within the physiological [Ca2+]i range, the protonation state of the primary Ca2+-binding sites influences Ca2+ binding and regulates TMEM16F activation. Our findings thus uncover a regulatory mechanism of TMEM16F by pHi and shine light on our understanding of the pathophysiological roles of TMEM16F in diseases with dysregulated pHi, including cancer.

Duke Scholars

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Published In

J Gen Physiol

DOI

EISSN

1540-7748

Publication Date

February 1, 2021

Volume

153

Issue

2

Location

United States

Related Subject Headings

  • Physiology
  • Phospholipid Transfer Proteins
  • Ion Transport
  • Hydrogen-Ion Concentration
  • Humans
  • HIV Infections
  • Calcium
  • Anoctamins
  • 3208 Medical physiology
  • 3109 Zoology
 

Citation

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Liang, P., & Yang, H. (2021). Molecular underpinning of intracellular pH regulation on TMEM16F. J Gen Physiol, 153(2). https://doi.org/10.1085/jgp.202012704
Liang, Pengfei, and Huanghe Yang. “Molecular underpinning of intracellular pH regulation on TMEM16F.J Gen Physiol 153, no. 2 (February 1, 2021). https://doi.org/10.1085/jgp.202012704.
Liang P, Yang H. Molecular underpinning of intracellular pH regulation on TMEM16F. J Gen Physiol. 2021 Feb 1;153(2).
Liang, Pengfei, and Huanghe Yang. “Molecular underpinning of intracellular pH regulation on TMEM16F.J Gen Physiol, vol. 153, no. 2, Feb. 2021. Pubmed, doi:10.1085/jgp.202012704.
Liang P, Yang H. Molecular underpinning of intracellular pH regulation on TMEM16F. J Gen Physiol. 2021 Feb 1;153(2).

Published In

J Gen Physiol

DOI

EISSN

1540-7748

Publication Date

February 1, 2021

Volume

153

Issue

2

Location

United States

Related Subject Headings

  • Physiology
  • Phospholipid Transfer Proteins
  • Ion Transport
  • Hydrogen-Ion Concentration
  • Humans
  • HIV Infections
  • Calcium
  • Anoctamins
  • 3208 Medical physiology
  • 3109 Zoology