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

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  • Kathryn H. Gunn

    (University of North Carolina)

  • Saskia B. Neher

    (University of North Carolina)

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.

Suggested Citation

  • Kathryn H. Gunn & Saskia B. Neher, 2023. "Structure of dimeric lipoprotein lipase reveals a pore adjacent to the active site," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38243-9
    DOI: 10.1038/s41467-023-38243-9
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    1. Adar Sonn-Segev & Katarina Belacic & Tatyana Bodrug & Gavin Young & Ryan T. VanderLinden & Brenda A. Schulman & Johannes Schimpf & Thorsten Friedrich & Phat Vinh Dip & Thomas U. Schwartz & Benedikt Ba, 2020. "Quantifying the heterogeneity of macromolecular machines by mass photometry," Nature Communications, Nature, vol. 11(1), pages 1-10, December.
    2. Tristan Bepler & Kotaro Kelley & Alex J. Noble & Bonnie Berger, 2020. "Topaz-Denoise: general deep denoising models for cryoEM and cryoET," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
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    1. Sriram Aiyer & Philip R. Baldwin & Shi Min Tan & Zelin Shan & Juntaek Oh & Atousa Mehrani & Marianne E. Bowman & Gordon Louie & Dario Oliveira Passos & Selena Đorđević-Marquardt & Mario Mietzsch & Jos, 2024. "Overcoming resolution attenuation during tilted cryo-EM data collection," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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