title: Influence of apolipoprotein (Apo) A-I structure on nascent high density lipoprotein (HDL) particle size distribution.
abstract: The principal protein of high density lipoprotein (HDL), apolipoprotein (apo) A-I, in the lipid-free state contains two tertiary structure domains comprising an N-terminal helix bundle and a less organized C-terminal domain. It is not known how the properties of these domains modulate the formation and size distribution of apoA-I-containing nascent HDL particles created by ATP-binding cassette transporter A1 (ABCA1)-mediated efflux of cellular phospholipid and cholesterol. To address this issue, proteins corresponding to the two domains of human apoA-I (residues 1-189 and 190-243) and mouse apoA-I (residues 1-186 and 187-240) together with some human/mouse domain hybrids were examined for their abilities to form HDL particles when incubated with either ABCA1-expressing cells or phospholipid multilamellar vesicles. Incubation of human apoA-I with cells gave rise to two sizes of HDL particles (hydrodynamic diameter, 8 and 10 nm), and removal or disruption of the C-terminal domain eliminated the formation of the smaller particle. Variations in apoA-I domain structure and physical properties exerted similar effects on the rates of formation and sizes of HDL particles created by either spontaneous solubilization of phospholipid multilamellar vesicles or the ABCA1-mediated efflux of cellular lipids. It follows that the sizes of nascent HDL particles are determined at the point at which cellular phospholipid and cholesterol are solubilized by apoA-I; apparently, this is the rate-determining step in the overall ABCA1-mediated cellular lipid efflux process. The stability of the apoA-I N-terminal helix bundle domain and the hydrophobicity of the C-terminal domain are important determinants of both nascent HDL particle size and their rate of formation.
authors.affiliation: Lipid Research Group, Gastroenterology, Hepatology, and Nutrition Division, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-4318, USA.
authors.forename: Charulatha
authors.initials: C
authors.lastname: Vedhachalam
authors.forename: Palaniappan Sevugan
authors.initials: PS
authors.lastname: Chetty
authors.forename: Margaret
authors.initials: M
authors.lastname: Nickel
authors.forename: Padmaja
authors.initials: P
authors.lastname: Dhanasekaran
authors.forename: Sissel
authors.initials: S
authors.lastname: Lund-Katz
authors.forename: George H
authors.initials: GH
authors.lastname: Rothblat
authors.forename: Michael C
authors.initials: MC
authors.lastname: Phillips
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016632:Apolipoprotein A-I / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D006801:Humans; D008075:Lipoproteins, HDL / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D051379:Mice; D010316:Particle Size; D011487:Protein Conformation
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D008075:Lipoproteins, HDL; D002784:Cholesterol