Structure of lipoprotein lipase in complex with GPIHBP1

Arora, Rishi; Nimonkar, Amitabh V.; Baird, Daniel; Wang, Chunhua; Chiu, Chun-Hao; Horton, Patricia A.; Hanrahan, Susan; Cubbon, Rose; Weldon, Stephen; Tschantz, William R.; Mueller, Sascha; Brunner, Reto; Lehr, Philipp; Meier, Peter; Ottl, Johannes; Voznesensky, Andrei; Pandey, Pramod; Smith, Thomas M.; Stojanovic, Aleksandar; Flyer, Alec; Benson, Timothy E.; Romanowski, Michael J.; Trauger, John W.

doi:10.1073/pnas.1820171116

Structure of lipoprotein lipase in complex with GPIHBP1

Journal Article · Thu May 09 00:00:00 EDT 2019 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1820171116· OSTI ID:1526064

Arora, Rishi ^[1]; Nimonkar, Amitabh V. ^[1]; Baird, Daniel ^[1]; Wang, Chunhua ^[1]; Chiu, Chun-Hao ^[1]; Horton, Patricia A. ^[1]; Hanrahan, Susan ^[1]; Cubbon, Rose ^[1]; Weldon, Stephen ^[1]; Tschantz, William R. ^[1]; Mueller, Sascha ^[1]; Brunner, Reto ^[2]; Lehr, Philipp ^[1]; Meier, Peter ^[1]; Ottl, Johannes ^[2]; Voznesensky, Andrei ^[1]; Pandey, Pramod ^[1]; Smith, Thomas M. ^[1]; Stojanovic, Aleksandar ^[1]; Flyer, Alec ^[1] more »

Novartis Inst. for Biomedical Research, Cambridge, MA (United States)
Chemical Biology and Therapeutics, Basel (Switzerland)

Lipoprotein lipase (LPL) plays a central role in triglyceride (TG) metabolism. By catalyzing the hydrolysis of TGs present in TG-rich lipoproteins (TRLs), LPL facilitates TG utilization and regulates circulating TG and TRL concentrations. Until very recently, structural information for LPL was limited to homology models, presumably due to the propensity of LPL to unfold and aggregate. By coexpressing LPL with a soluble variant of its accessory protein glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1) and with its chaperone protein lipase maturation factor 1 (LMF1), we obtained a stable and homogenous LPL/GPIHBP1 complex that was suitable for structure determination. We report here X-ray crystal structures of human LPL in complex with human GPIHBP1 at 2.5–3.0 Å resolution, including a structure with a novel inhibitor bound to LPL. Binding of the inhibitor resulted in ordering of the LPL lid and lipid-binding regions and thus enabled determination of the first crystal structure of LPL that includes these important regions of the protein. It was assumed for many years that LPL was only active as a homodimer. The structures and additional biochemical data reported here are consistent with a new report that LPL, in complex with GPIHBP1, can be active as a monomeric 1:1 complex. The crystal structures illuminate the structural basis for LPL-mediated TRL lipolysis as well as LPL stabilization and transport by GPIHBP1.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1526064

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 21 Vol. 116; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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A lipoprotein lipase–GPI-anchored high-density lipoprotein–binding protein 1 fusion lowers triglycerides in mice: Implications for managing familial chylomicronemia syndrome Nimonkar, Amitabh V.; Weldon, Stephen; Godbout, Kevin Journal of Biological Chemistry, Vol. 295, Issue 10 https://doi.org/10.1074/jbc.ra119.011079	journal	October 2019
Unfolding of monomeric lipoprotein lipase by ANGPTL4: Insight into the regulation of plasma triglyceride metabolism Kristensen, Kristian K.; Leth-Espensen, Katrine Zinck; Mertens, Haydyn D. T. Proceedings of the National Academy of Sciences, Vol. 117, Issue 8 https://doi.org/10.1073/pnas.1920202117	journal	February 2020
Angiopoietin-like proteins as therapeutic targets for cardiovascular disease: focus on lipid disorders Morelli, Marco Bruno; Chavez, Christopher; Santulli, Gaetano Expert Opinion on Therapeutic Targets, Vol. 24, Issue 1 https://doi.org/10.1080/14728222.2020.1707806	journal	January 2020

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59 BASIC BIOLOGICAL SCIENCES
GPIHBP1
LPL
X-ray crystallography
lipase

Structure of lipoprotein lipase in complex with GPIHBP1

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References (33)

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