The brown adipocyte protein CIDEA promotes lipid droplet fusion via a phosphatidic acid-binding amphipathic helix

  1. David Barneda
  2. Joan Planas-Iglesias
  3. Maria L Gaspar
  4. Dariush Mohammadyani
  5. Sunil Prasannan
  6. Dirk Dormann
  7. Gil-Soo Han
  8. Stephen A Jesch
  9. George M Carman
  10. Valerian Kagan
  11. Malcolm G Parker
  12. Nicholas T Ktistakis
  13. Ann M Dixon
  14. Judith Klein-Seetharaman
  15. Susan Henry
  16. Mark Christian  Is a corresponding author
  1. Imperial College London, United Kingdom
  2. University of Warwick, United Kingdom
  3. Cornell University, United States
  4. University of Pittsburgh, United States
  5. Imperial College London, United States
  6. Rutgers University, United States
  7. Babraham Institute, United Kingdom

Abstract

Maintenance of energy homeostasis depends on the highly regulated storage and release of triacylglycerol primarily in adipose tissue and excessive storage is a feature of common metabolic disorders. CIDEA is a lipid droplet (LD)-protein enriched in brown adipocytes promoting the enlargement of LDs which are dynamic, ubiquitous organelles specialized for storing neutral lipids. We demonstrate an essential role in this process for an amphipathic helix in CIDEA, which facilitates embedding in the LD phospholipid monolayer and binds phosphatidic acid (PA). LD pairs are docked by CIDEA trans-complexes through contributions of the N-terminal domain and a C-terminal dimerization region. These complexes, enriched at the LD-LD contact site, interact with the cone-shaped phospholipid PA and likely increase phospholipid barrier permeability, promoting LD fusion by transference of lipids. This physiological process is essential in adipocyte differentiation as well as serving to facilitate the tight coupling of lipolysis and lipogenesis in activated brown fat.

Article and author information

Author details

  1. David Barneda

    Institute of Reproductive and Developmental Biology, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Joan Planas-Iglesias

    Warwick Medical School, University of Warwick, Coventry, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Maria L Gaspar

    Department of Molecular Biology and Genetics, Cornell University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Dariush Mohammadyani

    Department of Bioengineering, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Sunil Prasannan

    Department of Chemistry, University of Warwick, Coventry, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Dirk Dormann

    Microscopy Facility, MRC Clinical Sciences Centre, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Gil-Soo Han

    Microscopy Facility, MRC Clinical Sciences Centre, Imperial College London, London, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Stephen A Jesch

    Department of Molecular Biology and Genetics, Cornell University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. George M Carman

    Department of Food Science, Rutgers Center for Lipid Research, Rutgers University, New Brunswick, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Valerian Kagan

    Department of Bioengineering, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Malcolm G Parker

    Institute of Reproductive and Developmental Biology, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  12. Nicholas T Ktistakis

    Signalling Programme, Babraham Institute, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  13. Ann M Dixon

    Department of Chemistry, University of Warwick, Coventry, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  14. Judith Klein-Seetharaman

    Warwick Medical School, University of Warwick, Coventry, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  15. Susan Henry

    Department of Molecular Biology and Genetics, Cornell University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Mark Christian

    Institute of Reproductive and Developmental Biology, Imperial College London, London, United Kingdom
    For correspondence
    m.christian@warwick.ac.uk
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Stephen G Young, University of California, Los Angeles, United States

Publication history

  1. Received: March 13, 2015
  2. Accepted: November 25, 2015
  3. Accepted Manuscript published: November 26, 2015 (version 1)
  4. Accepted Manuscript updated: December 10, 2015 (version 2)
  5. Version of Record published: February 3, 2016 (version 3)

Copyright

© 2015, Barneda 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

  • 4,202
    Page views
  • 1,096
    Downloads
  • 70
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, 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)

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

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

  1. David Barneda
  2. Joan Planas-Iglesias
  3. Maria L Gaspar
  4. Dariush Mohammadyani
  5. Sunil Prasannan
  6. Dirk Dormann
  7. Gil-Soo Han
  8. Stephen A Jesch
  9. George M Carman
  10. Valerian Kagan
  11. Malcolm G Parker
  12. Nicholas T Ktistakis
  13. Ann M Dixon
  14. Judith Klein-Seetharaman
  15. Susan Henry
  16. Mark Christian
(2015)
The brown adipocyte protein CIDEA promotes lipid droplet fusion via a phosphatidic acid-binding amphipathic helix
eLife 4:e07485.
https://doi.org/10.7554/eLife.07485

Further reading

    1. Structural Biology and Molecular Biophysics
    Christopher M Hoel, Lin Zhang, Stephen G Brohawn
    Research Article Updated

    TMEM87s are eukaryotic transmembrane proteins with two members (TMEM87A and TMEM87B) in humans. TMEM87s have proposed roles in protein transport to and from the Golgi, as mechanosensitive ion channels, and in developmental signaling. TMEM87 disruption has been implicated in cancers and developmental disorders. To better understand TMEM87 structure and function, we determined a cryo-EM structure of human TMEM87A in lipid nanodiscs. TMEM87A consists of a Golgi-dynamics (GOLD) domain atop a membrane-spanning seven-transmembrane helix domain with a large cavity open to solution and the membrane outer leaflet. Structural and functional analyses suggest TMEM87A may not function as an ion channel or G-protein coupled receptor. We find TMEM87A shares its characteristic domain arrangement with seven other proteins in humans; three that had been identified as evolutionary related (TMEM87B, GPR107, and GPR108) and four previously unrecognized homologs (GPR180, TMEM145, TMEM181, and WLS). Among these structurally related GOLD domain seven-transmembrane helix (GOST) proteins, WLS is best characterized as a membrane trafficking and secretion chaperone for lipidated Wnt signaling proteins. We find key structural determinants for WLS function are conserved in TMEM87A. We propose TMEM87A and structurally homologous GOST proteins could serve a common role in trafficking membrane-associated cargo.

    1. Immunology and Inflammation
    2. Structural Biology and Molecular Biophysics
    Rui Liu, Kangcheng Song ... Lei Chen
    Research Article Updated

    Phagocyte oxidase plays an essential role in the first line of host defense against pathogens. It oxidizes intracellular NADPH to reduce extracellular oxygen to produce superoxide anions that participate in pathogen killing. The resting phagocyte oxidase is a heterodimeric complex formed by two transmembrane proteins NOX2 and p22. Despite the physiological importance of this complex, its structure remains elusive. Here, we reported the cryo-EM structure of the functional human NOX2-p22 complex in nanodisc in the resting state. NOX2 shows a canonical 6-TM architecture of NOX and p22 has four transmembrane helices. M3, M4, and M5 of NOX2, and M1 and M4 helices of p22 are involved in the heterodimer formation. Dehydrogenase (DH) domain of NOX2 in the resting state is not optimally docked onto the transmembrane domain, leading to inefficient electron transfer and NADPH binding. Structural analysis suggests that the cytosolic factors might activate the NOX2-p22 complex by stabilizing the DH in a productive docked conformation.