8b40

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Structure of homomeric LRRC8C Volume-Regulated Anion Channel

Structural highlights

8b40 is a 7 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 4.6Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

LRC8C_MOUSE Non-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 (PubMed:29769723). The VRAC channel conducts iodide better than chloride and can also conduct organic osmolytes like taurine (By similarity). Plays a redundant role in the efflux of amino acids, such as aspartate and glutamate, in response to osmotic stress (By similarity). The VRAC channel also mediates transport of immunoreactive cyclic dinucleotide GMP-AMP (2'-3'-cGAMP), an immune messenger produced in response to DNA virus in the cytosol (By similarity). Channel activity requires LRRC8A plus at least one other family member (LRRC8B, LRRC8C, LRRC8D or LRRC8E); channel characteristics depend on the precise subunit composition (By similarity). May play a role in adipogenesis (PubMed:15184384, PubMed:15564382, PubMed:21804215).[UniProtKB:Q8TDW0][1] [2] [3] [4]

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[5]

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

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See Also

References

  1. ↑ Tominaga K, Kondo C, Kagata T, Hishida T, Nishizuka M, Imagawa M. The novel gene fad158, having a transmembrane domain and leucine-rich repeat, stimulates adipocyte differentiation. J Biol Chem. 2004 Aug 13;279(33):34840-8. doi: 10.1074/jbc.M312927200. Epub 2004 , Jun 7. PMID:15184384 doi:http://dx.doi.org/10.1074/jbc.M312927200
  2. ↑ Tominaga K, Johmura Y, Nishizuka M, Imagawa M. Fad24, a mammalian homolog of Noc3p, is a positive regulator in adipocyte differentiation. J Cell Sci. 2004 Dec 1;117(Pt 25):6217-26. PMID:15564382 doi:http://dx.doi.org/117/25/6217
  3. ↑ Hayashi T, Nozaki Y, Nishizuka M, Ikawa M, Osada S, Imagawa M. Factor for adipocyte differentiation 158 gene disruption prevents the body weight gain and insulin resistance induced by a high-fat diet. Biol Pharm Bull. 2011;34(8):1257-63. doi: 10.1248/bpb.34.1257. PMID:21804215 doi:http://dx.doi.org/10.1248/bpb.34.1257
  4. ↑ Deneka D, Sawicka M, Lam AKM, Paulino C, Dutzler R. Structure of a volume-regulated anion channel of the LRRC8 family. Nature. 2018 May 16. pii: 10.1038/s41586-018-0134-y. doi:, 10.1038/s41586-018-0134-y. PMID:29769723 doi:http://dx.doi.org/10.1038/s41586-018-0134-y
  5. ↑ 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

Contents


PDB ID 8b40

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OCA

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