6OAU

Apo Structure of WT Lipoprotein Lipase in Complex with GPIHBP1 Mutant N78D N82D produced in GnTI-deficient HEK293-F cells

Summary for 6OAU

• Entry DOI: 10.2210/pdb6oau/pdb
• Descriptor: Lipoprotein lipase, Glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• Functional Keywords: lipase, hydrolase-protein binding complex, hydrolase/protein binding
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 131452.81

Authors

Arora, R.,Horton, P.A.,Benson, T.E.,Romanowski, M.J. (deposition date: 2019-03-18, release date: 2019-05-08, Last modification date: 2023-10-11)

Primary citation

Arora, R.,Nimonkar, A.V.,Baird, D.,Wang, C.,Chiu, C.H.,Horton, P.A.,Hanrahan, S.,Cubbon, R.,Weldon, S.,Tschantz, W.R.,Mueller, S.,Brunner, R.,Lehr, P.,Meier, P.,Ottl, J.,Voznesensky, A.,Pandey, P.,Smith, T.M.,Stojanovic, A.,Flyer, A.,Benson, T.E.,Romanowski, M.J.,Trauger, J.W.
Structure of lipoprotein lipase in complex with GPIHBP1.
Proc.Natl.Acad.Sci.USA, 116:10360-10365, 2019

PubMed 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.

PubMed: 31072929
DOI: 10.1073/pnas.1820171116

Experimental method

X-RAY DIFFRACTION (2.48 Å)