title: Hot spots in apolipoprotein A-II misfolding and amyloidosis in mice and men.
abstract: ApoA-II is the second-major protein of high-density lipoproteins. C-terminal extension in human apoA-II or point substitutions in murine apoA-II cause amyloidosis. The molecular mechanism of apolipoprotein misfolding, from the native predominantly α-helical conformation to cross-β-sheet in amyloid, is unknown. We used 12 sequence-based prediction algorithms to identify two ten-residue segments in apoA-II that probably initiate β-aggregation. Previous studies of apoA-II fragments experimentally verify this prediction. Together, experimental and bioinformatics studies explain why the C-terminal extension in human apoA-II causes amyloidosis and why, unlike murine apoA-II, human apoA-II normally does not cause amyloidosis despite its unusually high sequence propensity for β-aggregation.
authors.affiliation: Department of Physiology and Biophysics, Boston University School of Medicine, W329, 700 Albany Street, Boston, MA 02118, United States. Electronic address: gursky@bu.edu.
authors.forename: Olga
authors.initials: O
authors.lastname: Gursky
mesh_terms: D000595:Amino Acid Sequence; D000686:Amyloidosis / Q000097:blood*; D000818:Animals; D016633:Apolipoprotein A-II / Q000097:blood* / Q000737:chemistry; D006801:Humans; D008075:Lipoproteins, HDL / Q000097:blood; D051379:Mice; D017510:Protein Folding; D017433:Protein Structure, Secondary
chemical_list: D016633:Apolipoprotein A-II; D008075:Lipoproteins, HDL
keywords: Amphipathic α-helix; Amyloidogenic mutations; High-density lipoprotein; Lipid surface binding proteins; α-helix to β-sheet conversion