Author:
Gunn Kathryn H.,Neher Saskia B.
Abstract
AbstractLipoprotein lipase (LPL) hydrolyzes triglycerides from circulating lipoproteins, releasing free fatty acids. Active LPL is needed to prevent hypertriglyceridemia, which is a risk factor for cardiovascular disease (CVD). Using cryogenic electron microscopy (cryoEM), we determined the structure of an active LPL dimer at 3.9 Å resolution. This structure reveals an open hydrophobic pore adjacent to the active site residues. Using modeling, we demonstrate that this pore can accommodate an acyl chain from a triglyceride. Known LPL mutations that lead to hypertriglyceridemia localize to the end of the pore and cause defective substrate hydrolysis. The pore may provide additional substrate specificity and/or allow unidirectional acyl chain release from LPL. This structure also revises previous models on how LPL dimerizes, revealing a C-terminal to C-terminal interface. We hypothesize that this active C-terminal to C-terminal conformation is adopted by LPL when associated with lipoproteins in capillaries.
Funder
U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute
U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences
American Heart Association
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
Cited by
3 articles.
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