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Papers In Press, published online ahead of print August 6, 2002
Department Pathology and Comparative Medicine, The Wake Forest University, Winston-Salem, NC 27157
Corresponding Author: msthomas{at}wfubmc.edu
Apolipoprotein A-I (apo A-I) readily forms discoidal HDL particles with phospholipids serving as an ideal transporter of plasma cholesterol. In the lipid-bound conformation, apo A-I activates the enzyme lecithin:cholesterol acyltransferase (LCAT) stimulating the formation of cholesterol esters (CE) from free cholesterol (FC). As esterification proceeds CEs accumulate within the hydrophobic core of the discoidal phospholipid bilayer transforming it into a spherical HDL particle. To investigate the change in apo A-I conformation as it adapts to a spherical surface, fluorescence resonance energy transfer studies were performed. Discoidal rHDL particles containing two lipid-bound apo A-I molecules were prepared with acceptor and donor fluorescent probes attached to cysteines residues located at specific positions. Fluorescence quenching was measured for probe combinations located within repeats 5 and 5 (residue 132), repeats 5 and 6 (residues 132 and 154) and repeats 6 and 6 (residue 154). Results from these experiments indicated that each of the 2 molecules of discoidal bound apo A-I exists in multiple conformations and support the concept of a "variable registry" rather than a "fixed helix-helix registry". Additionally, discoidal rHDL were transformed in vitro to core-containing particles by incubation with LCAT. Compositional analysis showed that core-containing particles contained 11% less phospholipid and 633% more cholesterol ester and a total of 3 apo A-I molecules per particle. Spherical particles showed a lowering of acceptor to donor probe quenching when compared to starting rHDL. Therefore, we conclude that as lipid-bound apo A-I adjusts from a discoidal to a spherical surface its intermolecular interactions are significantly reduced presumably to cover the increased surface area of the particle.
J. Biol. Chem, 10.1074/jbc.M206770200
Submitted on July 8, 2002
Revised on July 31, 2002
Accepted on August 6, 2002
Apo A-I structure on discs and spheres: Variable helix registry and conformational states
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