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TitleStructure of the human volume regulated anion channel.
Journal, issue, pagesElife, Vol. 7, Year 2018
Publish dateAug 10, 2018
AuthorsJennifer M Kefauver / Kei Saotome / Adrienne E Dubin / Jesper Pallesen / Christopher A Cottrell / Stuart M Cahalan / Zhaozhu Qiu / Gunhee Hong / Christopher S Crowley / Tess Whitwam / Wen-Hsin Lee / Andrew B Ward / Ardem Patapoutian /
PubMed AbstractSWELL1 (LRRC8A) is the only essential subunit of the Volume Regulated Anion Channel (VRAC), which regulates cellular volume homeostasis and is activated by hypotonic solutions. SWELL1, together with ...SWELL1 (LRRC8A) is the only essential subunit of the Volume Regulated Anion Channel (VRAC), which regulates cellular volume homeostasis and is activated by hypotonic solutions. SWELL1, together with four other LRRC8 family members, potentially forms a vastly heterogeneous cohort of VRAC channels with different properties; however, SWELL1 alone is also functional. Here, we report a high-resolution cryo-electron microscopy structure of full-length human homo-hexameric SWELL1. The structure reveals a trimer of dimers assembly with symmetry mismatch between the pore-forming domain and the cytosolic leucine-rich repeat (LRR) domains. Importantly, mutational analysis demonstrates that a charged residue at the narrowest constriction of the homomeric channel is an important pore determinant of heteromeric VRAC. Additionally, a mutation in the flexible N-terminal portion of SWELL1 affects pore properties, suggesting a putative link between intracellular structures and channel regulation. This structure provides a scaffold for further dissecting the heterogeneity and mechanism of activation of VRAC.
External linksElife / PubMed:30095067 / PubMed Central
MethodsEM (single particle)
Resolution4.4 Å
Structure data

EMDB-7935, PDB-6djb:
Structure of human Volume Regulated Anion Channel composed of SWELL1 (LRRC8A)
Method: EM (single particle) / Resolution: 4.4 Å

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / anion channel / LRRC8A / SWELL1

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