The Refined Structure of Nascent HDL Reveals A Key Functional Domain For Particle Maturation and Dysfunction
Document Type
Article
Publication Date
2007
Publication Title
Nature Structural & Molecular Biology
Abstract
The cardioprotective function of high-density lipoprotein (HDL) is largely attributed to its ability to facilitate transport of cholesterol from peripheral tissues to the liver. However, HDL may become dysfunctional through oxidative modification, impairing cellular cholesterol efflux. Here we report a refined molecular model of nascent discoidal HDL, determined using hydrogen-deuterium exchange mass spectrometry. The model reveals two apolipoprotein A1 (apoA1) molecules arranged in an antiparallel double-belt structure, with residues 159–180 of each apoA1 forming a protruding solvent-exposed loop. We further show that this loop, including Tyr166, a preferred target for site-specific oxidative modification within atheroma, directly interacts with and activates lecithin cholesterol acyl transferase. These studies identify previously uncharacterized structural features of apoA1 in discoidal HDL that are crucial for particle maturation, and elucidate a structural and molecular mechanism for generating a dysfunctional form of HDL in atherosclerosis.
Recommended Citation
Wu, Zhiping; Wagner, Matthew A.; Zheng, Lemin; Parks, John S.; Shy, Jacinto M. III; Smith, Jonathan D.; Gogonea, Valentin; and Hazen, Stanley L., "The Refined Structure of Nascent HDL Reveals A Key Functional Domain For Particle Maturation and Dysfunction" (2007). Chemistry Faculty Publications. 368.
https://engagedscholarship.csuohio.edu/scichem_facpub/368
DOI
10.1038/nsmb1284
Volume
14
