The acidic domain of the endothelial membrane protein GPIHBP1 stabilizes lipoprotein lipase activity by preventing unfolding of its catalytic domain

  1. Simon Mysling
  2. Kristian Kølby Kristensen
  3. Mikael Larsson
  4. Anne P Beigneux
  5. Henrik Gårdsvoll
  6. Fong G Loren
  7. André Bensadouen
  8. Thomas JD Jørgensen
  9. Stephen G Young
  10. Michael Ploug  Is a corresponding author
  1. Rigshospitalet, Denmark
  2. University of California, Los Angeles, United States
  3. Rigshospitalet, United States
  4. Cornell University, United States
  5. University of Southern Denmark, Denmark

Abstract

GPIHBP1 is a glycolipid-anchored membrane protein of capillary endothelial cells that binds lipoprotein lipase (LPL) within the interstitial space and shuttles it to the capillary lumen. The LPL•GPIHBP1 complex is responsible for margination of triglyceride-rich lipoproteins along capillaries and their lipolytic processing. The current work conceptualizes a model for the GPIHBP1•LPL interaction based on biophysical measurements with hydrogen-deuterium exchange/mass spectrometry, surface plasmon resonance, and zero-length cross-linking. According to this model, GPIHBP1 is comprised of two functionally distinct domains: (1) an intrinsically disordered acidic N-terminal domain; and (2) a folded C-terminal domain that tethers GPIHBP1 to the cell membrane by glycosylphosphatidylinositol. We demonstrate that these domains serve different roles in regulating the kinetics of LPL binding. Importantly, the acidic domain stabilizes LPL catalytic activity by mitigating the global unfolding of LPL's catalytic domain. This study provides a conceptual framework for understanding intravascular lipolysis and GPIHBP1 and LPL mutations causing familial chylomicronemia.

Article and author information

Author details

  1. Simon Mysling

    Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark
    Competing interests
    No competing interests declared.
  2. Kristian Kølby Kristensen

    Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark
    Competing interests
    No competing interests declared.
  3. Mikael Larsson

    Department of Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.
  4. Anne P Beigneux

    Department of Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.
  5. Henrik Gårdsvoll

    Finsen Laboratory, Rigshospitalet, Copenhagen, United States
    Competing interests
    No competing interests declared.
  6. Fong G Loren

    Department of Medicine, University of California, Los Angeles, Loa Angeles, United States
    Competing interests
    No competing interests declared.
  7. André Bensadouen

    Division of Nutritional Science, Cornell University, Ithaca, United States
    Competing interests
    No competing interests declared.
  8. Thomas JD Jørgensen

    Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark
    Competing interests
    No competing interests declared.
  9. Stephen G Young

    Department of Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    Stephen G Young, Reviewing editor, eLife.
  10. Michael Ploug

    Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark
    For correspondence
    m-ploug@finsenlab.dk
    Competing interests
    No competing interests declared.

Reviewing Editor

  1. Christopher K. Glass, University of California, San Diego, United States

Publication history

  1. Received: October 5, 2015
  2. Accepted: January 2, 2016
  3. Accepted Manuscript published: January 3, 2016 (version 1)
  4. Version of Record published: February 3, 2016 (version 2)
  5. Version of Record updated: May 9, 2016 (version 3)

Copyright

© 2016, Mysling 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. Simon Mysling
  2. Kristian Kølby Kristensen
  3. Mikael Larsson
  4. Anne P Beigneux
  5. Henrik Gårdsvoll
  6. Fong G Loren
  7. André Bensadouen
  8. Thomas JD Jørgensen
  9. Stephen G Young
  10. Michael Ploug
(2016)
The acidic domain of the endothelial membrane protein GPIHBP1 stabilizes lipoprotein lipase activity by preventing unfolding of its catalytic domain
eLife 5:e12095.
https://doi.org/10.7554/eLife.12095

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