气候变化领域集成服务门户(CCPortal): The intrinsic instability of the hydrolase domain of lipoprotein lipase facilitates its inactivation by ANGPTL4-catalyzed unfolding

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DOI	10.1073/pnas.2026650118
	The intrinsic instability of the hydrolase domain of lipoprotein lipase facilitates its inactivation by ANGPTL4-catalyzed unfolding
	Leth-Espensen K.Z.; Kristensen K.K.; Kumari A.; Winther A.-M.L.; Young S.G.; Jørgensen T.J.D.; Ploug M.
发表日期	2021
ISSN	00278424
卷号	118 期号:12
英文摘要	The complex between lipoprotein lipase (LPL) and its endothelial receptor (GPIHBP1) is responsible for the lipolytic processing of triglyceride-rich lipoproteins (TRLs) along the capillary lumen, a physiologic process that releases lipid nutrients for vital organs such as heart and skeletal muscle. LPL activity is regulated in a tissue-specific manner by endogenous inhibitors (angiopoietin-like [ANGPTL] proteins 3, 4, and 8), but the molecular mechanisms are incompletely understood. ANGPTL4 catalyzes the inactivation of LPL monomers by triggering the irreversible unfolding of LPL’s α/β-hydrolase domain. Here, we show that this unfolding is initiated by the binding of ANGPTL4 to sequences near LPL’s catalytic site, including β2, β3–α3, and the lid. Using pulse-labeling hydrogen‒deuterium exchange mass spectrometry, we found that ANGPTL4 binding initiates conformational changes that are nucleated on β3–α3 and progress to β5 and β4–α4, ultimately leading to the irreversible unfolding of regions that form LPL’s catalytic pocket. LPL unfolding is context dependent and varies with the thermal stability of LPL’s α/β-hydrolase domain (Tm of 34.8 °C). GPIHBP1 binding dramatically increases LPL stability (Tm of 57.6 °C), while ANGPTL4 lowers the onset of LPL unfolding by ∼20 °C, both for LPL and LPL•GPIHBP1 complexes. These observations explain why the binding of GPIHBP1 to LPL retards the kinetics of ANGPTL4-mediated LPL inactivation at 37 °C but does not fully suppress inactivation. The allosteric mechanism by which ANGPTL4 catalyzes the irreversible unfolding and inactivation of LPL is an unprecedented pathway for regulating intravascular lipid metabolism. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Intrinsic disorder \| HDX-MS \| intravascular lipolysis \| GPIHBP1 \| hypertriglyceridemia
语种	英语
scopus关键词	angiopoietin related protein; angiopoietin related protein 4; fatty acid; glycosylphosphatidylinositol anchored high density lipoprotein binding protein 1; glycosylphosphatidylinositol anchored protein; high density lipoprotein; hydrolase; lipoprotein; lipoprotein lipase; triacylglycerol; unclassified drug; allosterism; Article; controlled study; enzyme active site; enzyme activity; enzyme inactivation; enzyme stability; fat intake; fatty acid transport; hydrogen deuterium exchange-mass spectrometry; lipid metabolism; lipolysis; priority journal; protein binding; protein lipid interaction; protein localization; protein structure; protein unfolding; thermostability
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180152
作者单位	Finsen Laboratory, Rigshospitalet, Copenhagen N, DK-2200, Denmark; Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen N, DK-2200, Denmark; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense M, DK-5230, Denmark; Department of Medicine, University of California, Los Angeles, CA 90095, United States; Department of Human Genetics, University of California, Los Angeles, CA 90095, United States
推荐引用方式 GB/T 7714	Leth-Espensen K.Z.,Kristensen K.K.,Kumari A.,et al. The intrinsic instability of the hydrolase domain of lipoprotein lipase facilitates its inactivation by ANGPTL4-catalyzed unfolding[J],2021,118(12).
APA	Leth-Espensen K.Z..,Kristensen K.K..,Kumari A..,Winther A.-M.L..,Young S.G..,...&Ploug M..(2021).The intrinsic instability of the hydrolase domain of lipoprotein lipase facilitates its inactivation by ANGPTL4-catalyzed unfolding.Proceedings of the National Academy of Sciences of the United States of America,118(12).
MLA	Leth-Espensen K.Z.,et al."The intrinsic instability of the hydrolase domain of lipoprotein lipase facilitates its inactivation by ANGPTL4-catalyzed unfolding".Proceedings of the National Academy of Sciences of the United States of America 118.12(2021).