Journal article
A retractable lid in lecithin: Cholesterol acyltransferase provides a structural mechanism for activation by apolipoprotein A-I
KA Manthei, J Ahn, A Glukhova, W Yuan, C Larkin, TD Manett, L Chang, JA Shayman, MJ Axley, A Schwendeman, JJG Tesmer
Journal of Biological Chemistry | AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC | Published : 2017
Abstract
Lecithin:cholesterol acyltransferase (LCAT) plays a key role in reverse cholesterol transport by transferring an acyl group from phosphatidylcholine to cholesterol, promoting the maturation of high-density lipoproteins (HDL) from discoidal to spherical particles. LCAT is activated through an unknown mechanism by apolipoprotein A-I (apoA-I) and other mimetic peptides that form a belt around HDL. Here, we report the crystal structure of LCAT with an extended lid that blocks access to the active site, consistent with an inactive conformation. Residues Thr-123 and Phe-382 in the catalytic domain form a latch-like interaction with hydrophobic residues in the lid. Because these residues are mutate..
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Awarded by National Institutes of Health
Funding Acknowledgements
This work was supported by National Institutes of Health Grants HL071818 and HL122416 (to J. J. G. T.) and AR056991 (to J. A. S.), F32 Ruth L. Kirschstein NRSA F32HL131288 (to K. A. M.), American Heart Association Postdoctoral Fellowships 15POST24870001 (to K. A. M.) and 16POST27760002 (to W. Y.), American Heart Association Scientist Development Grant 13SDG17230049 (to A. S.), University of Michigan Chemical Biology Postdoctoral Fellowship (to A. G.), Veterans Affairs Merit Review Award 1I01BX002021 (to J. A. S.), and MedImmune. J. A., C. L., and M. J. A. declare that they are employees of MedImmune, the global biologics R&D arm of AstraZeneca, and own stock/stock options in AstraZeneca. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.