The allosteric mechanism leading to an open-groove lipid conductive state of the TMEM16F scramblase. Academic Article uri icon

Overview

abstract

  • TMEM16F is a Ca2+-activated phospholipid scramblase in the TMEM16 family of membrane proteins. Unlike other TMEM16s exhibiting a membrane-exposed hydrophilic groove that serves as a translocation pathway for lipids, the experimentally determined structures of TMEM16F shows the groove in a closed conformation even under conditions of maximal scramblase activity. It is currently unknown if/how TMEM16F groove can open for lipid scrambling. Here we describe the analysis of ~400 µs all-atom molecular dynamics (MD) simulations of the TMEM16F revealing an allosteric mechanism leading to an open-groove, lipid scrambling competent state of the protein. The groove opens into a continuous hydrophilic conduit that is highly similar in structure to that seen in other activated scramblases. The allosteric pathway connects this opening to an observed destabilization of the Ca2+ ion bound at the distal site near the dimer interface, to the dynamics of specific protein regions that produces the open-groove state to scramble phospholipids.

publication date

  • September 19, 2022

Research

keywords

  • Anoctamins
  • Phospholipid Transfer Proteins

Identity

PubMed Central ID

  • PMC9484709

Scopus Document Identifier

  • 85138166065

Digital Object Identifier (DOI)

  • 10.1007/BF01386390

PubMed ID

  • 36123525

Additional Document Info

volume

  • 5

issue

  • 1