7p5y

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Structure of homomeric LRRC8A Volume-Regulated Anion Channel in complex with synthetic nanobody Sb3

Structural highlights

7p5y is a 12 chain structure with sequence from Mus musculus and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Electron Microscopy, Resolution 3.29Å
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

Members of the LRRC8 family form heteromeric assemblies, which function as volume-regulated anion channels. These modular proteins consist of a transmembrane pore and cytoplasmic leucine-rich repeat (LRR) domains. Despite their known molecular architecture, the mechanism of activation and the role of the LRR domains in this process has remained elusive. Here we address this question by generating synthetic nanobodies, termed sybodies, which target the LRR domain of the obligatory subunit LRRC8A. We use these binders to investigate their interaction with homomeric LRRC8A channels by cryo-electron microscopy and the consequent effect on channel activation by electrophysiology. The five identified sybodies either inhibit or enhance activity by binding to distinct epitopes of the LRR domain, thereby altering channel conformations. In combination, our work provides a set of specific modulators of LRRC8 proteins and reveals the role of their cytoplasmic domains as regulators of channel activity by allosteric mechanisms.

Allosteric modulation of LRRC8 channels by targeting their cytoplasmic domains.,Deneka D, Rutz S, Hutter CAJ, Seeger MA, Sawicka M, Dutzler R Nat Commun. 2021 Sep 14;12(1):5435. doi: 10.1038/s41467-021-25742-w. PMID:34521847[3]

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

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See Also

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ Deneka D, Rutz S, Hutter CAJ, Seeger MA, Sawicka M, Dutzler R. Allosteric modulation of LRRC8 channels by targeting their cytoplasmic domains. Nat Commun. 2021 Sep 14;12(1):5435. PMID:34521847 doi:10.1038/s41467-021-25742-w

Contents


PDB ID 7p5y

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