The intrinsic instability of the hydrolase domain of lipoprotein lipase facilitates its inactivation by ANGPTL4-catalyzed unfolding
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
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发表时间：
2021-03-23
影响因子：
11.1
通讯作者：
Ploug, Michael
中科院分区：
文献类型：
--
作者：
Leth-Espensen, Katrine Z.;Kristensen, Kristian K.;Ploug, Michael
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 alpha/beta-hydrolase domain. Here, we show that this unfolding is initiated by the binding of ANGPTL4 to sequences near LPL's catalytic site, including beta 2, beta 3-alpha 3, and the lid. Using pulse-labeling hydrogen-deuterium exchange mass spectrometry, we found that ANGPTL4 binding initiates conformational changes that are nucleated on beta 3 alpha 3 and progress to beta 5 and beta 4-alpha 4, 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 alpha/beta-hydrolase domain (T-m of 34.8 degrees C). GPIHBP1 binding dramatically increases LPL stability (T-m of 57.6 degrees C), while ANGPTL4 lowers the onset of LPL unfolding by similar to 20 degrees 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 degrees 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.
