The acidic domain of the endothelial membrane protein GPIHBP1 stabilizes lipoprotein lipase activity by preventing unfolding of its catalytic domain
Simon Mysling,
Kristian Kølby Kristensen,
Mikael Larsson,
Anne P Beigneux,
Henrik Gårdsvoll,
Loren G Fong,
André Bensadouen,
Thomas JD Jørgensen,
Stephen G Young,
Michael Ploug
Affiliations
Simon Mysling
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
Kristian Kølby Kristensen
Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark; Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
Mikael Larsson
Department of Medicine, University of California, Los Angeles, Los Angeles, United States
Anne P Beigneux
Department of Medicine, University of California, Los Angeles, Los Angeles, United States
Henrik Gårdsvoll
Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark; Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
Loren G Fong
Department of Medicine, University of California, Los Angeles, Los Angeles, United States
André Bensadouen
Division of Nutritional Science, Cornell University, Ithaca, United States
Thomas JD Jørgensen
Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark
Stephen G Young
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
Michael Ploug
Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark; Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
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 comprises 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.
