title: Significance of Lipid-Free and Lipid-Associated ApoA-I in Cellular Cho-lesterol Efflux.
abstract: The structure and stability of apolipoprotein (apo)A-I, the major apolipoprotein of human plasma high-density lipoproteins (HDL), determine the efficiency of the protein in the process of HDL generation and affect HDL properties in binding and exchanging its constituents, thus playing an essential role in reverse cholesterol transport. The equilibrium stability of an apoA-I molecule at the lipid interface (12.7 kcal/mol) predicted by a thermodynamic cycle for apolipoprotein folding-unfolding in water and at interface, largely exceeds apoA-I helix stability in HDL against chemical denaturation (3-5 kcal/mol). An ensemble of structures of lipid-bound apoA-I with different stabilities is assumed to exist. The conformational transitions between apoA-I conformers in water and lipid phases correspond to Lumry-Eyring model OL ⇔ CL ⇒ MW, where OL and CL are open and closed structures of HDLbound apoA-I, and MW is the molten globule in water. The model includes the reversible foldingunfolding transitions of N- and C-domains at HDL interface and apolipoprotein irreversible dissociation. We gathered published data on cholesterol efflux for apoA-I proteins with missense mutations in C-domain and calculated the stability of these mutants as a change of free energy relative to a wild type protein. Significant negative correlation was found between this stability and the efficiency of cAMP-stimulated cholesterol efflux. Thus, besides the known role of C-domain hydrophobicity, structure-destabilizing changes may significantly contribute to ABCA1-mediated cholesterol efflux by free apolipoprotein.
authors.affiliation: National Research Centre for Preventive Medicine, 10, Petroverigsky Street, 101990 Moscow, Russia.
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Dergunov
authors.forename: Evdokiya A
authors.initials: EA
authors.lastname: Garaeva
authors.forename: Eugeny V
authors.initials: EV
authors.lastname: Savushkin
authors.forename: Dmitry Y
authors.initials: DY
authors.lastname: Litvinov
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000737:chemistry* / Q000378:metabolism*; D001692:Biological Transport; D002784:Cholesterol / Q000378:metabolism*; D006801:Humans; D050356:Lipid Metabolism; D008055:Lipids / Q000737:chemistry*; D008074:Lipoproteins / Q000737:chemistry / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D055550:Protein Stability; D013329:Structure-Activity Relationship
chemical_list: D016632:Apolipoprotein A-I; D008055:Lipids; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D002784:Cholesterol