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Edited by Ian A. Wilson, The Scripps Research Institute, La Jolla, CA, and approved April 16, 2019 (received for review November 27, 2018)
Significance
LPL is the central enzyme in TG metabolism. We report here X-ray crystal structures of LPL in complex with its accessory protein GPIHBP1, including a structure with a novel inhibitor bound in the LPL active site. The inhibitor-bound structure includes the LPL lid and lipid-binding regions, which makes this the first complete crystal structure of LPL and provides insight into how these regions of LPL contribute to the recognition of TRL substrates. The structural evidence and additional biochemical experiments presented here are consistent with a newly published report that LPL, in complex with GPIHBP1, can be active as a monomeric 1:1 complex and, therefore, help overturn the long-standing assumption that LPL is only active as a homodimer.
Abstract
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.
Footnotes
↵1Present address: Casma Therapeutics, Cambridge, MA 02139.
↵2Present address: Experimental and Chemical Biology, Merck Exploratory Science Center, Cambridge, MA 02141.
- ↵3To whom correspondence may be addressed. Email: michael.romanowski{at}novartis.com or john.trauger{at}novartis.com.
Author contributions: D.B., P.L., P.M., J.O., A.V., P.P., T.M.S., A.S., A.F., T.E.B., M.J.R., and J.W.T. designed research; R.A., A.V.N., D.B., C.W., C.-H.C., P.A.H., S.H., R.C., S.W., W.R.T., S.M., R.B., P.L., and A.S. performed research; R.A., A.V.N., W.R.T., P.L., and J.O. analyzed data; and R.A., A.V.N., M.J.R., and J.W.T. wrote the paper.
Conflict of interest statement: All authors are current or former employees of Novartis Institutes for Biomedical Research or Novartis Pharma AG, and some are also shareholders of Novartis. This work was funded by Novartis Institutes for Biomedical Research.
This article is a PNAS Direct Submission.
Data deposition: The atomic coordinates and structure factors have been deposited in the Protein Data Bank, www.wwpdb.org (PDB ID codes 6OAZ, 6OAU, and 6OB0).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1820171116/-/DCSupplemental.
Published under the PNAS license.
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Structure of lipoprotein lipase in complex with GPIHBP1
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