2. Academic Validation
  3. A disordered acidic domain in GPIHBP1 harboring a sulfated tyrosine regulates lipoprotein lipase

A disordered acidic domain in GPIHBP1 harboring a sulfated tyrosine regulates lipoprotein lipase

  • Proc Natl Acad Sci U S A. 2018 Jun 26;115(26):E6020-E6029. doi: 10.1073/pnas.1806774115.
Kristian K Kristensen 1 2,  Søren Roi Midtgaard 3,  Simon Mysling 1 2 4,  Oleg Kovrov 5,  Lars Bo Hansen 6,  Nicholas Skar-Gislinge 3,  Anne P Beigneux 7,  Birthe B Kragelund 8,  Gunilla Olivecrona 5,  Stephen G Young 9 10,  Thomas J D Jørgensen 4,  Loren G Fong 7,  Michael Ploug 11 2
Affiliations

Affiliations

  • 1 Finsen Laboratory, Rigshospitalet, DK-2200 Copenhagen N, Denmark.
  • 2 Biotech Research and Innovation Centre, University of Copenhagen, DK-2200 Copenhagen N, Denmark.
  • 3 Structural Biophysics, Niels Bohr Institute, University of Copenhagen, DK-2100 Copenhagen Ø, Denmark.
  • 4 Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense M, Denmark.
  • 5 Department of Medical Biosciences, Umeå University, SE-901 87 Umeå, Sweden.
  • 6 Zealand Pharma, DK-2600 Glostrup, Denmark.
  • 7 Department of Medicine, University of California, Los Angeles, CA 90095.
  • 8 Department of Biology, University of Copenhagen, DK-2200 Copenhagen N, Denmark.
  • 9 Department of Medicine, University of California, Los Angeles, CA 90095; sgyoung@mednet.ucla.edu m-ploug@finsenlab.dk.
  • 10 Department of Human Genetics, University of California, Los Angeles, CA 90095.
  • 11 Finsen Laboratory, Rigshospitalet, DK-2200 Copenhagen N, Denmark; sgyoung@mednet.ucla.edu m-ploug@finsenlab.dk.
PMID: 29899144 DOI: 10.1073/pnas.1806774115
Abstract

The intravascular processing of triglyceride-rich lipoproteins depends on lipoprotein Lipase (LPL) and GPIHBP1, a membrane protein of endothelial cells that binds LPL within the subendothelial spaces and shuttles it to the capillary lumen. In the absence of GPIHBP1, LPL remains mislocalized within the subendothelial spaces, causing severe hypertriglyceridemia (chylomicronemia). The N-terminal domain of GPIHBP1, an intrinsically disordered region (IDR) rich in acidic residues, is important for stabilizing LPL's catalytic domain against spontaneous and ANGPTL4-catalyzed unfolding. Here, we define several important properties of GPIHBP1's IDR. First, a conserved tyrosine in the middle of the IDR is posttranslationally modified by O-sulfation; this modification increases both the affinity of GPIHBP1-LPL interactions and the ability of GPIHBP1 to protect LPL against ANGPTL4-catalyzed unfolding. Second, the acidic IDR of GPIHBP1 increases the probability of a GPIHBP1-LPL encounter via electrostatic steering, increasing the association rate constant (kon) for LPL binding by >250-fold. Third, we show that LPL accumulates near capillary endothelial cells even in the absence of GPIHBP1. In wild-type mice, we expect that the accumulation of LPL in close proximity to capillaries would increase interactions with GPIHBP1. Fourth, we found that GPIHBP1's IDR is not a key factor in the pathogenicity of chylomicronemia in patients with the GPIHBP1 autoimmune syndrome. Finally, based on biophysical studies, we propose that the negatively charged IDR of GPIHBP1 traverses a vast space, facilitating capture of LPL by capillary endothelial cells and simultaneously contributing to GPIHBP1's ability to preserve LPL structure and activity.

Keywords

autoimmune disease; electrostatic steering; hypertriglyceridemia; intravascular lipolysis; intrinsically disordered region.

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