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Structural basis for anion conduction in the calcium-activated chloride channel TMEM16A.

<div class='caption-title'>(A) Ribbon representation of the mTMEM16A dimer with the EM density (contoured at 11σ) superimposed. (B) Superposition of mTMEM16A (blue and red) and nhTMEM16 (beige and grey). A and B, The view is from within the membrane with the extracellular side at the top. The membrane boundary is indicated.</div>
<div class='caption-title'>Sequences of mTMEM16A(ac) (UniProt Q8BHY3.2) and nhTMEM16 (NCBI Reference Sequence: XM_003045982.1) were aligned with Clustal Omega (Sievers et al., 2011) and edited manually based on the nhTMEM16 structure (PDBID 4WIS). Identical residues are highlighted in green, homologous residues in yellow and residues of the Ca2+ binding site in red. Secondary structure elements of nhTMEM16 are indicated below. The numbering corresponds to mTMEM16A. () Indicates mutated positions of the narrow neck and (▲) of the intracellular vestibule.</div>
<div class='caption-title'>(A) Gel-filtration profile of purified and de-glycosylated mTMEM16A run on a Superdex200 column equilibrated with the detergent digitonin. (B) SDS-PAGE gel of the concentrated peak fractions used for cryo-EM sample preparation. mTMEM16A is labeled (*). The molecular weight of marker proteins (kDa) is indicated. (C) Representative micrograph of purified mTMEM16A in vitreous ice. (D) Representative images of 2D class averages from two-dimensional classification in RELION.</div>
Paulino C, Neldner Y, Lam AK, Kalienkova V, Brunner JD, Schenck S, Dutzler R
OpenAccess logo Elife 6 (2017)
Cited: 79 times
EuropePMC logo PMID: 28561733

Abstract

The calcium-activated chloride channel TMEM16A is a member of a conserved protein family that comprises ion channels and lipid scramblases. Although the structure of the scramblase nhTMEM16 has defined the architecture of the family, it was unknown how a channel has adapted to cope with its distinct functional properties. Here we have addressed this question by the structure determination of mouse TMEM16A by cryo-electron microscopy and a complementary functional characterization. The protein shows a similar organization to nhTMEM16, except for changes at the site of catalysis. There, the conformation of transmembrane helices constituting a membrane-spanning furrow that provides a path for lipids in scramblases has changed to form an enclosed aqueous pore that is largely shielded from the membrane. Our study thus reveals the structural basis of anion conduction in a TMEM16 channel and it defines the foundation for the diverse functional behavior in the TMEM16 family.

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  1. Recent progress in structural studies on TMEM16A channel. Shi S, Pang C, Guo S, Chen Y, Ma B, Qu C, Ji Q, An H. Comput Struct Biotechnol J 18 714-722 (2020)

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  3. Known structures and unknown mechanisms of TMEM16 scramblases and channels. Falzone ME, Malvezzi M, Lee BC, Lee BC, Accardi A. J Gen Physiol 150 933-947 (2018)
  4. TMEM16A in Cystic Fibrosis: Activating or Inhibiting? Kunzelmann K, Ousingsawat J, Cabrita I, Doušová T, Bähr A, Janda M, Schreiber R, Benedetto R. Front Pharmacol 10 3 (2019)
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  18. TMEM16A/ANO1: Current Strategies and Novel Drug Approaches for Cystic Fibrosis. Mitri C, Sharma H, Corvol H, Tabary O. Cells 10 2867 (2021)
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  20. Structure and Function of Calcium-Activated Chloride Channels and Phospholipid Scramblases in the TMEM16 Family. Nguyen DM, Chen TY. Handb Exp Pharmacol 283 153-180 (2024)

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