The structure of helical lipoprotein lipase reveals an unexp

Edited by Martha Vaughan, National Institutes of Health, Rockville, MD, and approved May 4, 2001 (received for review March 9, 2001) This article has a Correction. Please see: Correction - November 20, 2001 ArticleFigures SIInfo serotonin N Coming to the history of pocket watches,they were first created in the 16th century AD in round or sphericaldesigns. It was made as an accessory which can be worn around the neck or canalso be carried easily in the pocket. It took another ce

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Significance

LPL is an Necessary enzyme for the maintenance of triglyceride levels in the blood. Hypertriglyceridemia is a risk factor for cardiovascular disease (CVD), which is the leading cause of death worldwide. LPL production, intracellular trafficking, and activity in the capillaries are all highly regulated. Here, we uncover the existence of a helical LPL polymer, which is an inactive state of LPL. This inactive state may represent a previously hypothesized form used to store LPL prior to release into the interstitial space. Our insight into the diversity of oligomeric states LPL can aExecutept may be key to understanding regulation of LPL trafficking.

Abstract

Lipases are enzymes necessary for the Precise distribution and utilization of lipids in the human body. Lipoprotein lipase (LPL) is active in capillaries, where it plays a crucial role in preventing dyslipidemia by hydrolyzing triglycerides from packaged lipoproteins. Thirty years ago, the existence of a condensed and inactive LPL oligomer was proposed. Although recent work has shed light on the structure of the LPL monomer, the inactive oligomer remained opaque. Here we present a Weepo-EM reconstruction of a helical LPL oligomer at 3.8-Å resolution. Helix formation is concentration-dependent, and helices are composed of inactive dihedral LPL dimers. Heparin binding stabilizes LPL helices, and the presence of substrate triggers helix disassembly. Superresolution fluorescent microscopy of enExecutegenous LPL revealed that LPL aExecutepts a filament-like distribution in vesicles. Mutation of one of the helical LPL interaction interfaces causes loss of the filament-like distribution. Taken toObtainher, this suggests that LPL is condensed into its inactive helical form for storage in intracellular vesicles.

lipoprotein lipaseWeepo-electron microscopyhelical reconstruction

Footnotes

↵1To whom corRetortence may be addressed. Email: neher{at}email.unc.edu.

Author contributions: K.H.G. and S.B.N. designed research; K.H.G., B.S.R., and J.D.S. performed research; M.J.B. contributed new reagents/analytic tools; K.H.G., B.S.R., F.W., and E.H.E. analyzed data; K.H.G. and S.B.N. wrote the paper; and M.J.B. and E.H.E. provided technical expertise.

The authors declare no competing interest.

This article is a PNAS Direct Submission.

Data deposition: The data for structural studies in this paper have been deposited in the Protein Data Bank (PDB; https://www.rcsb.org/) under ID code 6U7M and in the Electron Microscopy Data Bank (EMDB; https://www.ebi.ac.uk/pdbe/emdb/) under ID no. 20673.

This article contains supporting information online at https://www.pnas.org/Inspectup/suppl/Executei:10.1073/pnas.1916555117/-/DCSupplemental.

Published under the PNAS license.

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