6e7k
From Proteopedia
Structure of the lipoprotein lipase GPIHBP1 complex that mediates plasma triglyceride hydrolysis
Structural highlights
Disease[LIPL_HUMAN] Hyperlipoproteinemia type 5;Familial lipoprotein lipase deficiency. The disease is caused by mutations affecting the gene represented in this entry. [HDBP1_HUMAN] Familial chylomicronemia syndrome. The disease is caused by mutations affecting the gene represented in this entry. Function[LIPL_HUMAN] The primary function of this lipase is the hydrolysis of triglycerides of circulating chylomicrons and very low density lipoproteins (VLDL) (PubMed:27578112). Binding to heparin sulfate proteogylcans at the cell surface is vital to the function. The apolipoprotein, APOC2, acts as a coactivator of LPL activity in the presence of lipids on the luminal surface of vascular endothelium (By similarity).[1] [2] [HDBP1_HUMAN] Plays a key role in the lipolytic processing of chylomicrons. Required for the transport of lipoprotein lipase LPL into the capillary lumen (By similarity). Publication Abstract from PubMedLipoprotein lipase (LPL) is responsible for the intravascular processing of triglyceride-rich lipoproteins. The LPL within capillaries is bound to GPIHBP1, an endothelial cell protein with a three-fingered LU domain and an N-terminal intrinsically disordered acidic domain. Loss-of-function mutations in LPL or GPIHBP1 cause severe hypertriglyceridemia (chylomicronemia), but structures for LPL and GPIHBP1 have remained elusive. Inspired by our recent discovery that GPIHBP1's acidic domain preserves LPL structure and activity, we crystallized an LPL-GPIHBP1 complex and solved its structure. GPIHBP1's LU domain binds to LPL's C-terminal domain, largely by hydrophobic interactions. Analysis of electrostatic surfaces revealed that LPL contains a large basic patch spanning its N- and C-terminal domains. GPIHBP1's acidic domain was not defined in the electron density map but was positioned to interact with LPL's large basic patch, providing a likely explanation for how GPIHBP1 stabilizes LPL. The LPL-GPIHBP1 structure provides insights into mutations causing chylomicronemia. Structure of the lipoprotein lipase-GPIHBP1 complex that mediates plasma triglyceride hydrolysis.,Birrane G, Beigneux AP, Dwyer B, Strack-Logue B, Kristensen KK, Francone OL, Fong LG, Mertens HDT, Pan CQ, Ploug M, Young SG, Meiyappan M Proc Natl Acad Sci U S A. 2018 Dec 17. pii: 1817984116. doi:, 10.1073/pnas.1817984116. PMID:30559189[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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