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Stepwise activation mechanism of the scramblase nhTMEM16 revealed by cryo-EM.

<div class='caption-title'>Cryo-EM structures of nhTMEM16 in detergent.</div>
<div class='caption-title'>Reconstitution of nhTMEM16 into liposomes.</div>
<div class='caption-title'>Structure Determination of nhTMEM16 in DDM in complex with Ca2+.</div>
Kalienkova V, Clerico Mosina V, Bryner L, Oostergetel GT, Dutzler R, Paulino C
OpenAccess logo Elife 8 (2019)
Related entries: 6qm4, 6qm5, 6qm6, 6qm9, 6qmb

Cited: 60 times
EuropePMC logo PMID: 30785398

Abstract

Scramblases catalyze the movement of lipids between both leaflets of a bilayer. Whereas the X-ray structure of the protein nhTMEM16 has previously revealed the architecture of a Ca2+-dependent lipid scramblase, its regulation mechanism has remained elusive. Here, we have used cryo-electron microscopy and functional assays to address this question. Ca2+-bound and Ca2+-free conformations of nhTMEM16 in detergent and lipid nanodiscs illustrate the interactions with its environment and they reveal the conformational changes underlying its activation. In this process, Ca2+ binding induces a stepwise transition of the catalytic subunit cavity, converting a closed cavity that is shielded from the membrane in the absence of ligand, into a polar furrow that becomes accessible to lipid headgroups in the Ca2+-bound state. Additionally, our structures demonstrate how nhTMEM16 distorts the membrane at both entrances of the subunit cavity, thereby decreasing the energy barrier for lipid movement.

Articles - 6qma mentioned but not cited (6)

  1. Cryo-EM structures and functional characterization of the murine lipid scramblase TMEM16F. Alvadia C, Lim NK, Clerico Mosina V, Oostergetel GT, Dutzler R, Paulino C. Elife 8 e44365 (2019)
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  3. Dynamic modulation of the lipid translocation groove generates a conductive ion channel in Ca2+-bound nhTMEM16. Khelashvili G, Falzone ME, Cheng X, Lee BC, Accardi A, Weinstein H. Nat Commun 10 4972 (2019)
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  5. Functional consequences of Genetics variant in TMC1 and TMC2 within a United Arab Emirates family with Pre-lingual hearing loss. Al Mutery A, Kamal Eldin Mohamed W, Mahfood M, Chouchen J, Tlili A. Saudi J Biol Sci 30 103520 (2023)
  6. research-article Structural basis of closed groove scrambling by a TMEM16 protein. Feng Z, Alvarenga OE, Accardi A. bioRxiv 2023.08.11.553029 (2024)


Reviews citing this publication (12)

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Articles citing this publication (42)

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