Seipin transmembrane segments critically function in triglyceride nucleation and lipid droplet budding from the membrane

  1. Siyoung Kim
  2. Jeeyun Chung
  3. Henning Arlt
  4. Alexander J Pak
  5. Robert V Farese Jnr
  6. Tobias C Walther
  7. Gregory A Voth  Is a corresponding author
  1. University of Chicago, United States
  2. Harvard T H Chan School of Public Health, United States
  3. Colorado School of Mines, United States
  4. Howard Hughes Medical Institute, Harvard T H Chan School of Public Health, United States

Abstract

Lipid droplets (LDs) are organelles formed in the endoplasmic reticulum (ER) to store triacylglycerol (TG) and sterol esters. The ER protein seipin is key for LD biogenesis. Seipin forms a cage-like structure, with each seipin monomer containing a conserved hydrophobic helix (HH) and two transmembrane (TM) segments. How the different parts of seipin function in TG nucleation and LD budding is poorly understood. Here, we utilized molecular dynamics simulations of human seipin, along with cell-based experiments, to study seipin's functions in protein-lipid interactions, lipid diffusion, and LD maturation. An all-atom (AA) simulation indicates that seipin TM segment residues and hydrophobic helices residues located in the phospholipid (PL) tail region of the bilayer attract TG. Simulating larger, growing LDs with coarse-grained (CG) models, we find that the seipin TM segments form a constricted neck structure to facilitate conversion of a flat oil lens into a budding LD. Using cell experiments and simulations, we also show that conserved, positively charged residues at the end of seipin's TM segments affect LD maturation. We propose a model in which seipin TM segments critically function in TG nucleation and LD growth.

Data availability

Numerical data represented as a graph in this manuscript are available at github.com/ksy141/seipin.

Article and author information

Author details

  1. Siyoung Kim

    Pritzker School of Molecular Engineering, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Jeeyun Chung

    Department of Molecular Metabolism, Harvard T H Chan School of Public Health, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Henning Arlt

    Department of Molecular Metabolism, Harvard T H Chan School of Public Health, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Alexander J Pak

    Department of Chemical and Biological Engineering, Colorado School of Mines, Golden, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Robert V Farese Jnr

    Department of Molecular Metabolism, Harvard T H Chan School of Public Health, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8103-2239
  6. Tobias C Walther

    Howard Hughes Medical Institute, Harvard T H Chan School of Public Health, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Gregory A Voth

    Department of Chemistry, University of Chicago, Chicago, United States
    For correspondence
    gavoth@uchicago.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3267-6748

Funding

National Institutes of Health

  • Robert V Farese Jnr
  • Tobias C Walther
  • Gregory A Voth

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

Reviewing Editor

  1. Lucie Delemotte, KTH Royal Institute of Technology, Sweden

Version history

  1. Received: November 24, 2021
  2. Preprint posted: December 6, 2021 (view preprint)
  3. Accepted: April 22, 2022
  4. Accepted Manuscript published: May 18, 2022 (version 1)
  5. Version of Record published: May 20, 2022 (version 2)

Copyright

© 2022, Kim 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.

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  1. Siyoung Kim
  2. Jeeyun Chung
  3. Henning Arlt
  4. Alexander J Pak
  5. Robert V Farese Jnr
  6. Tobias C Walther
  7. Gregory A Voth
(2022)
Seipin transmembrane segments critically function in triglyceride nucleation and lipid droplet budding from the membrane
eLife 11:e75808.
https://doi.org/10.7554/eLife.75808

Share this article

https://doi.org/10.7554/eLife.75808

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