Recent Advances in the Structural Biology of the Volume-Regulated Anion Channel LRRC8

Members of the leucine-rich repeat-containing 8 (LRRC8) protein family, composed of five LRRC8A-E isoforms, are pore-forming components of the volume-regulated anion channel (VRAC), which is activated by cell swelling and releases chloride ions (Cl − ) or other osmolytes to counteract cell swelling....

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Vydáno v:Frontiers in pharmacology Ročník 13; s. 896532
Hlavní autoři: Kasuya, Go, Nureki, Osamu
Médium: Journal Article
Jazyk:angličtina
Vydáno: Switzerland Frontiers Media S.A 11.05.2022
Témata:
cell volume homeostasis
cryo-EM
LRRC8
Pharmacology
structural biology
VRAC
structural biology
LRRC8
cryo-EM
VRAC
cell volume homeostasis
ISSN:1663-9812, 1663-9812
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Popis
Shrnutí:Members of the leucine-rich repeat-containing 8 (LRRC8) protein family, composed of five LRRC8A-E isoforms, are pore-forming components of the volume-regulated anion channel (VRAC), which is activated by cell swelling and releases chloride ions (Cl − ) or other osmolytes to counteract cell swelling. Although the LRRC8 protein family was identified as the molecular entity of VRAC only in 2014, due to recent advances in cryo-electron microscopy (cryo-EM), various LRRC8 structures, including homo-hexameric LRRC8A and LRRC8D structures, as well as inhibitor-bound and synthetic single-domain antibody-bound homo-hexameric LRRC8A structures, have been reported, thus extending our understanding of the molecular mechanisms of this protein family. In this review, we describe the important features of LRRC8 provided by these structures, particularly the overall architectures, and the suggested mechanisms underlying pore inhibition and allosteric modulation by targeting the intracellular leucine-rich repeat (LRR) domain.
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ORCID: Go Kasuya orcid.org/0000-0003-1756-5764; Osamu Nureki orcid.org/0000-0003-1813-7008
This article was submitted to Pharmacology of Ion Channels and Channelopathies, a section of the journal Frontiers in Pharmacology
Reviewed by: Tobias Stauber, Medical School Hamburg, Germany
Edited by: Huaizong Shen, Westlake University, China
Raimund Dutzler, University of Zurich, Switzerland
ISSN:1663-9812
1663-9812
DOI:10.3389/fphar.2022.896532