Structure of dimeric lipoprotein lipase reveals a pore adjacent to the active site

Kathryn H. Gunn and Saskia B. Neher ()
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Kathryn H. Gunn: University of North Carolina
Saskia B. Neher: University of North Carolina

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract Lipoprotein 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.

Date: 2023
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DOI: 10.1038/s41467-023-38243-9

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