1. Structural Biology and Molecular Biophysics
Download icon

Cryo-EM structures and functional characterization of the murine lipid scramblase TMEM16F

  1. Carolina Alvadia
  2. Novandy K Lim
  3. Vanessa Clerico Mosina
  4. Gert T Oostergetel
  5. Raimund Dutzler  Is a corresponding author
  6. Cristina Paulino  Is a corresponding author
  1. University of Zürich, Switzerland
  2. University of Groningen, Netherlands
Research Article
  • Cited 6
  • Views 2,220
  • Annotations
Cite this article as: eLife 2019;8:e44365 doi: 10.7554/eLife.44365

Abstract

The lipid scramblase TMEM16F initiates blood coagulation by catalyzing the exposure of phosphatidylserine in platelets. The protein is part of a family of membrane proteins, which encompasses calcium-activated channels for ions and lipids. Here, we reveal features of murine TMEM16F (mTMEM16F) that underlie its function as a lipid scramblase and an ion channel. The cryo-EM data of mTMEM16F in absence and presence of Ca2+ define the ligand-free closed conformation of the protein and the structure of a Ca2+-bound intermediate. Both conformations resemble their counterparts of the scrambling-incompetent anion channel mTMEM16A, yet with distinct differences in the region of ion and lipid permeation. In conjunction with functional data, we demonstrate the relationship between ion conduction and lipid scrambling. Although activated by a common mechanism, both functions appear to be mediated by alternate protein conformations that are at equilibrium in the ligand-bound state.

Article and author information

Author details

  1. Carolina Alvadia

    Department of Biochemistry, University of Zürich, Zürich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8446-1098
  2. Novandy K Lim

    Department of Biochemistry, University of Zürich, Zürich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5098-929X
  3. Vanessa Clerico Mosina

    Department of Structural Biology, University of Groningen, Groningen, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8013-0144
  4. Gert T Oostergetel

    Department of Structural Biology, University of Groningen, Groningen, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  5. Raimund Dutzler

    Department of Biochemistry, University of Zürich, Zürich, Switzerland
    For correspondence
    dutzler@bioc.uzh.ch
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2193-6129
  6. Cristina Paulino

    Department of Structural Biology, University of Groningen, Groningen, Netherlands
    For correspondence
    c.paulino@rug.nl
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7017-109X

Funding

Nederlandse Organisatie voor Wetenschappelijk Onderzoek (740.018.016)

  • Cristina Paulino

H2020 European Research Council (339116)

  • Raimund Dutzler

H2020 European Research Council (AnoBest)

  • Raimund Dutzler

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Kenton Jon Swartz, National Institute of Neurological Disorders and Stroke, National Institutes of Health, United States

Publication history

  1. Received: December 12, 2018
  2. Accepted: February 19, 2019
  3. Accepted Manuscript published: February 20, 2019 (version 1)
  4. Version of Record published: March 12, 2019 (version 2)

Copyright

© 2019, Alvadia et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 2,220
    Page views
  • 467
    Downloads
  • 6
    Citations

Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Structural Biology and Molecular Biophysics
    Zainab Ahdash et al.
    Short Report Updated
    1. Neuroscience
    2. Structural Biology and Molecular Biophysics
    Wenlei Ye et al.
    Research Article