Journal
STRUCTURE
Volume 29, Issue 12, Pages 1410-+Publisher
CELL PRESS
DOI: 10.1016/j.str.2021.07.009
Keywords
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Funding
- CPRIT Core Facility Support Award [RP170644]
- NIH [P01 HL020948, R01 GM134700, R01 GM135343]
- Endowed Scholars Program in Medical Science of UT Southwestern Medical Center
- O'Donnell Junior Faculty Funds
- Welch Foundation [I-1957]
- Damon Runyon Cancer Research Foundation [DRR-53S-19]
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Research on ACAT2 structure reveals similar membrane topology to ACAT1, with a cholesterol entry site and an activation site; Mutations in these entry or activation sites were found to attenuate ACAT2 activity, providing insights for designing new inhibitors for cardiovascular disease prevention.
Endoplasmic reticulum-localized acyl-CoA:cholesterol acyltransferases (ACAT), including ACAT1 and ACAT2, convert cholesterol to cholesteryl esters that become incorporated into lipoproteins or stored in cytosolic lipid droplets. Selective inhibition of ACAT2 has been shown to considerably attenuate hypercholesterolemia and atherosclerosis in mice. Here, we report cryogenic electron microscopy structures of human ACAT2 bound to its specific inhibitor pyripyropene A or the general ACAT inhibitor nevanimibe. Structural analysis reveals that ACAT2 has a topology in membranes similar to that of ACAT1 A catalytic core with an entry site occupied by a cholesterol molecule and another site for allosteric activation of ACAT2 is observed in these structures. Enzymatic assays show that mutations within sites of cholesterol entry or allosteric activation attenuate ACAT2 activity in vitro. Together, these results reveal mechanisms for ACAT2-mediated esterification of cholesterol, providing a blueprint to design new ACAT2 inhibitors for use in the prevention of cardiovascular disease.
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