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

Simon Mysling,Anne P Beigneux,André Bensadouen,Loren G Fong,Thomas Jd Jørgensen,Stephen G Young,Mikael Larsson,Michael Ploug,Henrik Gårdsvoll,Kristian Kølby Kristensen

doi:10.7554/elife.12095

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 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.

Highlights

We have known that lipoprotein lipase (LPL), a triglyceride hydrolase secreted by myocytes and adipocytes, is essential for the lipolytic processing of triglyceride-rich lipoproteins (TRLs) in the bloodstream (Korn, 1955; Young and Zechner, 2013)
The interaction between LPL and glycosylphosphatidylinositol-anchored high density lipoprotein–binding protein 1 (GPIHBP1) is essential for lipolysis of TRLs along the capillary lumen (Beigneux et al, 2007; Davies et al, 2010; Goulbourne et al, 2014)
In the absence of functional GPIHBP1, LPL is mislocalized within the interstitial spaces, leading to severe hypertriglyceridemia and reduced delivery of lipid nutrients to parenchymal cells (Goulbourne et al, 2014; Young and Zechner, 2013)

Summary

Introduction

We have known that lipoprotein lipase (LPL), a triglyceride hydrolase secreted by myocytes and adipocytes, is essential for the lipolytic processing of triglyceride-rich lipoproteins (TRLs) in the bloodstream (Korn, 1955; Young and Zechner, 2013). LPL-mediated processing of TRLs occurs along the capillary lumen, and LPL is readily released from the surface of capillaries with polyanionic compounds such as heparin. LPL contains an N-terminal domain (NTD) for catalysis and a C-terminal domain (CTD) that is essential for lipid binding. In the presence of certain LPL mutations (e.g., mutations in the catalytic triad or mutations that prevent LPL dimerization), the processing of TRLs is markedly impaired, leading to severe hypertriglyceridemia (familial chylomicronemia) (Brahm and Hegele, 2015)

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