Structure of lipoprotein lipase in complex with GPIHBP1
Structure of lipoprotein lipase in complex with GPIHBP1
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DOI：
10.1073/pnas.1820171116
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发表时间：
2019-05-21
影响因子：
11.1
通讯作者：
Trauger, John W.
中科院分区：
文献类型：
--
作者：
Arora, Rishi;Nimonkar, Amitabh V.;Trauger, John W.
脂蛋白脂肪酶（LPL）在甘油三酯（TG）代谢中起着核心作用。通过催化富含 TG 的脂蛋白 (TRL) 中存在的 TG 的水解，LPL 促进 TG 的利用并调节循环 TG 和 TRL 浓度。直到最近，LPL 的结构信息仅限于同源模型，大概是由于 LPL 具有展开和聚集的倾向。通过将 LPL 与其辅助蛋白糖基磷脂酰肌醇锚定的高密度脂蛋白结合蛋白 1 (GPIHBP1) 的可溶性变体及其伴侣蛋白脂肪酶成熟因子 1 (LMF1) 共表达，我们获得了稳定且均质的 LPL/GPIHBP1 复合物，适合结构测定。我们在此报告了人 LPL 与人 GPIHBP1 复合物的 X 射线晶体结构，分辨率为 2.5-3.0 A，其中包括与 LPL 结合的新型抑制剂的结构。抑制剂的结合导致 LPL 盖和脂质结合区域的排序，从而能够确定包括蛋白质的这些重要区域的 LPL 的第一个晶体结构。多年来，人们一直认为 LPL 仅作为同型二聚体具有活性。这里报告的结构和其他生化数据与新报告一致，即 LPL 与 GPIHBP1 复合，可以作为单体 1:1 复合物发挥活性。晶体结构阐明了 LPL 介导的 TRL 脂肪分解以及 GPIHBP1 稳定和运输 LPL 的结构基础。
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 A 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.