Hot spots in apolipoprotein A-II misfolding and amyloidosis in mice and men

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 alpha-helical conformation to cross-beta-sheet in amyloid, is unknown. We used 12 sequence-based prediction algorithms to identify two tenresidue segments in apoA-II that probably initiate beta-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 beta-aggregation. (C) 2014 Federation of European Biochemical Societies. Published by Elsevier B. V. All rights reserved.