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8b42

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Structure of heteromeric LRRC8A/C Volume-Regulated Anion Channel.

Structural highlights

8b42 is a 6 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 6.6Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

LRC8A_MOUSE Essential component of the volume-regulated anion channel (VRAC, also named VSOAC channel), an anion channel required to maintain a constant cell volume in response to extracellular or intracellular osmotic changes. The VRAC channel conducts iodide better than chloride and may also conduct organic osmolytes like taurine. Required for channel activity, together with at least one other family member (LRRC8B, LRRC8C, LRRC8D or LRRC8E); channel characteristics depend on the precise subunit composition. Can form functional channels by itself (in vitro) (By similarity). Involved in B-cell development: required for the pro-B cell to pre-B cell transition (PubMed:14660746, PubMed:24752297). Also required for T-cell development (PubMed:24752297).[UniProtKB:Q8IWT6]^[1] ^[2]

Publication Abstract from PubMed

Volume-regulated anion channels (VRACs) participate in the cellular response to osmotic swelling. These membrane proteins consist of heteromeric assemblies of LRRC8 subunits, whose compositions determine permeation properties. Although structures of the obligatory LRRC8A, also referred to as SWELL1, have previously defined the architecture of VRACs, the organization of heteromeric channels has remained elusive. Here we have addressed this question by the structural characterization of murine LRRC8A/C channels. Like LRRC8A, these proteins assemble as hexamers. Despite 12 possible arrangements, we find a predominant organization with an A:C ratio of two. In this assembly, four LRRC8A subunits cluster in their preferred conformation observed in homomers, as pairs of closely interacting proteins that stabilize a closed state of the channel. In contrast, the two interacting LRRC8C subunits show a larger flexibility, underlining their role in the destabilization of the tightly packed A subunits, thereby enhancing the activation properties of the protein.

Structure of a volume-regulated heteromeric LRRC8A/C channel.,Rutz S, Deneka D, Dittmann A, Sawicka M, Dutzler R Nat Struct Mol Biol. 2023 Jan;30(1):52-61. doi: 10.1038/s41594-022-00899-0. Epub , 2022 Dec 15. PMID:36522427^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Sawada A, Takihara Y, Kim JY, Matsuda-Hashii Y, Tokimasa S, Fujisaki H, Kubota K, Endo H, Onodera T, Ohta H, Ozono K, Hara J. A congenital mutation of the novel gene LRRC8 causes agammaglobulinemia in humans. J Clin Invest. 2003 Dec;112(11):1707-13. doi: 10.1172/JCI18937. PMID:14660746 doi:http://dx.doi.org/10.1172/JCI18937
↑ Kumar L, Chou J, Yee CS, Borzutzky A, Vollmann EH, von Andrian UH, Park SY, Hollander G, Manis JP, Poliani PL, Geha RS. Leucine-rich repeat containing 8A (LRRC8A) is essential for T lymphocyte development and function. J Exp Med. 2014 May 5;211(5):929-42. doi: 10.1084/jem.20131379. Epub 2014 Apr 21. PMID:24752297 doi:http://dx.doi.org/10.1084/jem.20131379
↑ Rutz S, Deneka D, Dittmann A, Sawicka M, Dutzler R. Structure of a volume-regulated heteromeric LRRC8A/C channel. Nat Struct Mol Biol. 2023 Jan;30(1):52-61. PMID:36522427 doi:10.1038/s41594-022-00899-0