title: Helical domains that mediate lipid solubilization and ABCA1-specific cholesterol efflux in apolipoproteins C-I and A-II.
abstract: Many of the apolipoproteins in HDL can elicit cholesterol efflux via ABCA1, a critical initial step in HDL formation. Recent work has indicated that omnipresent amphipathic helices play a critical role, and these have been studied intensively in the most common HDL protein, apolipoprotein (apo)A-I. However, little information exists about helical domain arrangement in other apolipoproteins. We studied two of the smallest apolipoproteins known to interact with ABCA1, human apoA-II and apoC-I, in terms of ability to reorganize phospholipid (PL) bilayers and to promote ABCA1-mediated cholesterol. We found that both proteins contained helical domains that were fast and slow with respect to solubilizing PL. ABCA1-medated efflux required a minimum of a bihelical polypeptide comprised of at least one each of a slow and fast lipid reorganizing domain. In both proteins, the fast helix was located at the C terminus preceded by a slow helix. Helical placement in apoC-I was not critical for ABCA1 activity, but helix swaps in apoA-II dramatically disrupted cholesterol efflux, indicating that the tertiary structure of the longer apolipoprotein is important for the pathway. This work has implications for a more complete molecular understanding of apolipoprotein-mediated cholesterol efflux.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Loren E
authors.initials: LE
authors.lastname: Smith
authors.forename: Jere P
authors.initials: JP
authors.lastname: Segrest
authors.forename: W Sean
authors.initials: WS
authors.lastname: Davidson
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000737:chemistry*; D016633:Apolipoprotein A-II / Q000737:chemistry*; D053302:Apolipoprotein C-I / Q000737:chemistry* / Q000235:genetics; D002784:Cholesterol / Q000737:chemistry*; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry; D010743:Phospholipids / Q000737:chemistry*; D017354:Point Mutation; D012995:Solubility
chemical_list: C577836:ABCA1 protein, human; C115794:APOA2 protein, human; C505803:APOC1 protein, human; D064286:ATP Binding Cassette Transporter 1; D016633:Apolipoprotein A-II; D053302:Apolipoprotein C-I; D008051:Lipid Bilayers; D010743:Phospholipids; D002784:Cholesterol
keywords: amphipathic helix; apolipoprotein-mediated cholesterol efflux; tertiary structure