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XB-ART-56932
Elife January 1, 2020; 9

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

Leisle L , Xu Y , Fortea E , Lee S , Galpin JD , Vien M , Ahern CA , Accardi A , Bernèche S .


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.

PubMed ID: 32343228
PMC ID: PMC7274781
Article link: Elife
Grant support: [+]

Species referenced: Xenopus
Genes referenced: aopep phex tpd52l2


Article Images: [+] show captions
References [+] :
Accardi, Secondary active transport mediated by a prokaryotic homologue of ClC Cl- channels. 2004, Pubmed