Hot spots in apolipoprotein A-II misfolding and amyloidosis in mice and men |
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Authors: | Olga Gursky |
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Affiliation: | Department of Physiology and Biophysics, Boston University School of Medicine, W329, 700 Albany Street, Boston, MA 02118, United States |
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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. |
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Keywords: | apo, apolipoprotein AApoAII, apoA-II amyloidosis HDL, high-density lipoproteins sHDL, spherical high-density lipoprotein dHDL, discoidal high-density lipoprotein HDL(A-I), HDL containing apoA-I as its sole protein HDL(A-II), HDL containing apoA-II as its sole protein HDL(A-I/A-II), HDL containing both apoA-I and apoA-II WT, wild type |
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