CryoEM structures of the human CLC-2 voltage-gated chloride channel reveal a ball-and-chain gating mechanism

Xu, Mengyuan; Neelands, Torben; Powers, Alexander S.; Liu, Yan; Miller, Steven D.; Pintilie, Grigore D.; Bois, J. Du; Dror, Ron O.; Chiu, Wah; Maduke, Merritt

doi:10.7554/elife.90648

Title: CryoEM structures of the human CLC-2 voltage-gated chloride channel reveal a ball-and-chain gating mechanism

Journal Article · 11 February 2024 · eLife

DOI: https://doi.org/10.7554/elife.90648 · OSTI ID:2403395

^[1]; Neelands, Torben ^[2]; Powers, Alexander S. ^[2]; Liu, Yan ^[3]; Miller, Steven D. ^[2]; Pintilie, Grigore D. ^[2]; Bois, J. Du ^[2];

^[2];

^[3];

^[2]

Stanford Univ., CA (United States); SLAC
Stanford Univ., CA (United States)
SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States); Stanford Univ., CA (United States)

CLC-2 is a voltage-gated chloride channel that contributes to electrical excitability and ion homeostasis in many different tissues. Among the nine mammalian CLC homologs, CLC-2 is uniquely activated by hyperpolarization, rather than depolarization, of the plasma membrane. The molecular basis for the divergence in polarity of voltage gating among closely related homologs has been a long-standing mystery, in part because few CLC channel structures are available. Here, we report cryoEM structures of human CLC-2 at 2.46 – 2.76 Å, in the presence and absence of the selective inhibitor AK-42. AK-42 binds within the extracellular entryway of the Cl^–-permeation pathway, occupying a pocket previously proposed through computational docking studies. In the apo structure, we observed two distinct conformations involving rotation of one of the cytoplasmic C-terminal domains (CTDs). In the absence of CTD rotation, an intracellular N-terminal 15-residue hairpin peptide nestles against the TM domain to physically occlude the Cl^–-permeation pathway. This peptide is highly conserved among species variants of CLC-2 but is not present in other CLC homologs. Previous studies suggested that the N-terminal domain of CLC-2 influences channel properties via a “ball-and-chain” gating mechanism, but conflicting data cast doubt on such a mechanism, and thus the structure of the N-terminal domain and its interaction with the channel has been uncertain. Through electrophysiological studies of an N-terminal deletion mutant lacking the 15-residue hairpin peptide, we support a model in which the N-terminal hairpin of CLC-2 stabilizes a closed state of the channel by blocking the cytoplasmic Cl^–-permeation pathway.

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Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC); National Institutes of Health (NIH)

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 2403395

Journal Information:: eLife, Journal Name: eLife Vol. 12; ISSN 2050-084X

Publisher:: eLife Sciences Publications, Ltd.Copyright Statement

Country of Publication:: United States

Language:: English

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Title: CryoEM structures of the human CLC-2 voltage-gated chloride channel reveal a ball-and-chain gating mechanism

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