Structural stability and functional remodeling of high-density lipoproteins.
Lipoproteins are protein-lipid nanoparticles that transport lipids in circulation and are central in atherosclerosis and other disorders of lipid metabolism. Apolipoproteins form flexible structural scaffolds and important functional ligands on the particle surface and direct lipoprotein metabolism. Lipoproteins undergo multiple rounds of metabolic remodeling that is crucial to lipid transport. Important aspects of this remodeling, including apolipoprotein dissociation and particle fusion, are mimicked in thermal or chemical denaturation and are modulated by free energy barriers. Here we review the biophysical studies that revealed the kinetic mechanism of lipoprotein stabilization and unraveled its structural basis. The main focus is on high-density lipoprotein (HDL). An inverse correlation between stability and functions of various HDLs in cholesterol transport suggests the functional role of structural disorder. A mechanism for the conformational adaptation of the major HDL proteins, apoA-I and apoA-II, to the increasing lipid load is proposed. Together, these studies help understand why HDL forms discrete subclasses separated by kinetic barriers, which have distinct composition, conformation and functional properties. Understanding these properties may help improve HDL quality and develop novel therapies for cardiovascular disease.
Department of Physiology & Biophysics, Boston University School of Medicine, W329, 700 Albany St., Boston, MA 02118, USA. Electronic address: gursky@bu.edu.
Olga
O
Gursky
D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry* / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000737:chemistry* / Q000378:metabolism; D008954:Models, Biological; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D055550:Protein Stability; D013816:Thermodynamics
D008051:Lipid Bilayers; D008075:Lipoproteins, HDL
Cholesterol transport and metabolism; Conformational ensemble; Lipid surface-binding proteins; Thermodynamic and kinetic stability