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.
Keywords: apoA-I, high density lipoprotein, missense mutation, protein stability, reverse cholesterol transport, structure prediction.
Rights & PermissionsPrintExport