2. Academic Validation
  3. The angiopoietin-like protein ANGPTL4 catalyzes unfolding of the hydrolase domain in lipoprotein lipase and the endothelial membrane protein GPIHBP1 counteracts this unfolding

The angiopoietin-like protein ANGPTL4 catalyzes unfolding of the hydrolase domain in lipoprotein lipase and the endothelial membrane protein GPIHBP1 counteracts this unfolding

  • Elife. 2016 Dec 8;5:e20958. doi: 10.7554/eLife.20958.
Simon Mysling 1 2 3,  Kristian Kølby Kristensen 1 2,  Mikael Larsson 4,  Oleg Kovrov 5,  André Bensadouen 6,  Thomas Jd Jørgensen 3,  Gunilla Olivecrona 5,  Stephen G Young 4 7,  Michael Ploug 1 2
Affiliations

Affiliations

  • 1 Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark.
  • 2 Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.
  • 3 Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark.
  • 4 Department of Medicine, University of California, Los Angeles, Los Angeles, United States.
  • 5 Department of Medical Biosciences, Umeå University, Umeå, Sweden.
  • 6 Division of Nutritional Science, Cornell University, Ithaca, United States.
  • 7 Department of Human Genetics, University of California, Los Angeles, Los Angeles, United States.
PMID: 27929370 DOI: 10.7554/eLife.20958
Abstract

Lipoprotein Lipase (LPL) undergoes spontaneous inactivation via global unfolding and this unfolding is prevented by GPIHBP1 (Mysling et al., 2016). We now show: (1) that ANGPTL4 inactivates LPL by catalyzing the unfolding of its hydrolase domain; (2) that binding to GPIHBP1 renders LPL largely refractory to this inhibition; and (3) that both the LU domain and the intrinsically disordered acidic domain of GPIHBP1 are required for this protective effect. Genetic studies have found that a common polymorphic variant in ANGPTL4 results in lower plasma triglyceride levels. We now report: (1) that this ANGPTL4 variant is less efficient in catalyzing the unfolding of LPL; and (2) that its Glu-to-Lys substitution destabilizes its N-terminal α-helix. Our work elucidates the molecular basis for regulation of LPL activity by ANGPTL4, highlights the physiological relevance of the inherent instability of LPL, and sheds LIGHT on the molecular defects in a clinically relevant variant of ANGPTL4.

Keywords

ANGTPL3; ANGTPL4; GPIHBP1; HDX-MS; biophysics; familial chylomicronemia; human; human biology; medicine; protein unfolding; structural biology.

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