Divergent Cl- and H+ pathways underlie transport coupling and gating in CLC exchangers and channels. Academic Article uri icon

Overview

abstract

  • The CLC family comprises H+-coupled exchangers and Cl- channels, and mutations causing their dysfunction lead to genetic disorders. The CLC exchangers, unlike canonical 'ping-pong' antiporters, simultaneously bind and translocate substrates through partially congruent pathways. How ions of opposite charge bypass each other while moving through a shared pathway remains unknown. Here, we use MD simulations, biochemical and electrophysiological measurements to identify two conserved phenylalanine residues that form an aromatic pathway whose dynamic rearrangements enable H+ movement outside the Cl- pore. These residues are important for H+ transport and voltage-dependent gating in the CLC exchangers. The aromatic pathway residues are evolutionarily conserved in CLC channels where their electrostatic properties and conformational flexibility determine gating. We propose that Cl- and H+ move through physically distinct and evolutionarily conserved routes through the CLC channels and transporters and suggest a unifying mechanism that describes the gating mechanism of both CLC subtypes.

publication date

  • April 28, 2020

Research

keywords

  • Antiporters
  • Chloride Channels
  • Chlorides
  • Ion Channel Gating
  • Ion Transport

Identity

PubMed Central ID

  • PMC7274781

Scopus Document Identifier

  • 85085052187

Digital Object Identifier (DOI)

  • 10.1016/j.bpj.2012.03.067

PubMed ID

  • 32343228

Additional Document Info

volume

  • 9