The intrinsic instability of the hydrolase domain of lipoprotein lipase facilitates its inactivation by ANGPTL4-catalyzed unfolding
Katrine Zinck Leth-Espensen, Kristian Kølby Kristensen, Anni Kumari, Anne-Marie Lund Winther, Stephen G. Young, Thomas J. D. Jørgensen, Michael Ploug
Abstract
Significance Dietary lipids are packaged into triglyceride-rich lipoprotein particles and delivered to many tissues via the bloodstream. A complex of lipoprotein lipase (LPL) and its endothelial cell receptor, GPIHBP1, hydrolyzes lipoprotein triglycerides, releasing fatty acids for uptake by surrounding cells. The efficiency of triglyceride hydrolysis is regulated by physiologic LPL inhibitors: ANGPTL-3, -4, and -8. We defined the binding site for ANGPTL4 on LPL and showed that ANGPTL4 induces allosteric changes in LPL that progress to irreversible unfolding and collapse of LPL’s catalytic site. The binding of GPIHBP1 to LPL augments LPL stability and renders LPL less susceptible to inactivation by ANGPTL4. Our studies provide crucial insights into molecular mechanisms that regulate intravascular triglyceride metabolism.