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The Role of Lipid-Free Apolipoprotein A-I and PCPE2 in HDL Metabolism

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abstract
The purpose of this work is to investigate the role of apolipoprotein apoA-I (apoA-I) and procollagen C-endopeptidase enhancer 2 (PCPE2) in high density lipoprotein (HDL) metabolism. ApoA-I comprises ~70 percent of the protein within HDL and has an essential role in cholesterol efflux from peripheral cells as part of the reverse cholesterol transport pathway. Lipid-free apoA-I undergoes conformational changes as HDL is formed, a poorly understood mechanism. We determined the structure of lipid-free apoA-I based on chemical cross-linking in conjunction with disulfide cross-linking to define distance constraints. Results indicate lipid-free apoA-I is compact with amino acids 44-186 bundled together with the N-and C-terminal ends folded so that they lie close to one another. We tested the accuracy of our model by determining the distance between two residues by engineering cysteine mutant apoA-I designed to “lock” or “unlock” by being within or exceeding 3-5 Å, respectively. These mutant apoA-I were used to assess the opening mechanism for lipid-free apoA-I lipidation to form recombinant HDL (rHDL) and nascent HDL (nHDL). Results of these studies identify central helices 4-6 as essential for rHDL and nHDL formation.
subject
ApoA-I
Atherosclerosis
HDL
PCPE2
contributor
Pollard, Ricquita DeAnn (author)
Sorci-Thomas, Mary G. (committee chair)
Lowther, W. Todd (committee member)
Hantgan, Roy R (committee member)
Parks, John S (committee member)
Thomas, Michael J (committee member)
date
2015-06-23T08:35:33Z (accessioned)
2015-06-23T08:35:33Z (available)
2015 (issued)
degree
Molecular Pathology (discipline)
identifier
http://hdl.handle.net/10339/57096 (uri)
language
en (iso)
publisher
Wake Forest University
title
The Role of Lipid-Free Apolipoprotein A-I and PCPE2 in HDL Metabolism
type
Dissertation

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