title: The angiopoietin-like protein ANGPTL4 catalyzes unfolding of the hydrolase domain in lipoprotein lipase and the endothelial membrane protein GPIHBP1 counteracts this unfolding.
abstract: Lipoprotein lipase (LPL) undergoes spontaneous inactivationviaglobal 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.
authors.affiliation: Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark.|Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.|Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark.
authors.forename: Simon
authors.initials: S
authors.lastname: Mysling
authors.affiliation: Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark.|Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Kristian Kølby
authors.initials: KK
authors.lastname: Kristensen
authors.affiliation: Department of Medicine, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Mikael
authors.initials: M
authors.lastname: Larsson
authors.affiliation: Department of Medical Biosciences, Umeå University, Umeå, Sweden.
authors.forename: Oleg
authors.initials: O
authors.lastname: Kovrov
authors.affiliation: Division of Nutritional Science, Cornell University, Ithaca, United States.
authors.forename: André
authors.initials: A
authors.lastname: Bensadouen
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark.
authors.forename: Thomas Jd
authors.initials: TJ
authors.lastname: Jørgensen
authors.affiliation: Department of Medical Biosciences, Umeå University, Umeå, Sweden.
authors.forename: Gunilla
authors.initials: G
authors.lastname: Olivecrona
authors.affiliation: Department of Medicine, University of California, Los Angeles, Los Angeles, United States.|Department of Human Genetics, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Young
authors.affiliation: Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark.|Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Michael
authors.identifier: 0000-0003-2215-4265
authors.initials: M
authors.lastname: Ploug
mesh_terms: D000075803:Angiopoietin-Like Protein 4 / Q000235:genetics / Q000378:metabolism*; D008071:Lipoprotein Lipase / Q000737:chemistry / Q000378:metabolism*; D013058:Mass Spectrometry; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D000072417:Protein Domains; D017510:Protein Folding; D025941:Protein Interaction Mapping; D018110:Receptors, Lipoprotein / Q000378:metabolism*
chemical_list: C474772:ANGPTL4 protein, human; D000075803:Angiopoietin-Like Protein 4; C523701:GPIHBP1 protein, human; D050505:Mutant Proteins; D018110:Receptors, Lipoprotein; D008071:Lipoprotein Lipase
keywords: ANGTPL3; ANGTPL4; GPIHBP1; HDX-MS; biophysics; familial chylomicronemia; human; human biology; medicine; protein unfolding; structural biology