Gating mechanism of the extracellular entry to the lipid pathway in a TMEM16 scramblase. Academic Article uri icon

Overview

abstract

  • Members of the TMEM16/ANO family of membrane proteins are Ca2+-activated phospholipid scramblases and/or Cl- channels. A membrane-exposed hydrophilic groove in these proteins serves as a shared translocation pathway for ions and lipids. However, the mechanism by which lipids gain access to and permeate through the groove remains poorly understood. Here, we combine quantitative scrambling assays and molecular dynamic simulations to identify the key steps regulating lipid movement through the groove. Lipid scrambling is limited by two constrictions defined by evolutionarily conserved charged and polar residues, one extracellular and the other near the membrane mid-point. The region between these constrictions is inaccessible to lipids and water molecules, suggesting that the groove is in a non-conductive conformation. A sequence of lipid-triggered reorganizations of interactions between these residues and the permeating lipids propagates from the extracellular entryway to the central constriction, allowing the groove to open and coordinate the headgroups of transiting lipids.

publication date

  • August 14, 2018

Research

keywords

  • Anoctamins
  • Extracellular Space
  • Ion Channel Gating
  • Lipids

Identity

PubMed Central ID

  • PMC6092359

Scopus Document Identifier

  • 85051644778

Digital Object Identifier (DOI)

  • 10.1021/jp401512z

PubMed ID

  • 30108217

Additional Document Info

volume

  • 9

issue

  • 1