期刊
BIOCHEMISTRY
卷 42, 期 3, 页码 672-678出版社
AMER CHEMICAL SOC
DOI: 10.1021/bi020429y
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资金
- NINDS NIH HHS [NS 38375] Funding Source: Medline
The conversion of alpha-synuclein into amyloid fibrils in the substantia nigra is linked to Parkinson's disease. alpha-Synuclein is natively unfolded in solution, but can be induced to form either alpha-helical or beta-sheet structure depending on its concentration and the solution conditions. The N-terminus of a-synuclein comprises seven 11-amino acid repeats (XKTKEGVXXXX) which can form an amphipathic alpha-helix. Why seven repeats, rather than six or eight, survived the evolutionary process is not clear. To probe this question, two sequence variants of alpha-synuclein, one with two fewer (del2) and one with two additional (plus2) repeats, were studied. As compared to wild-type alpha-synuclein, the plus2 variant disfavors the formation of beta-sheet-rich oligomers, including amyloid fibrils. In contrast, the truncated variant, del2, favors beta-sheet and fibril formation. We propose that the repeat number in WT alpha-synuclein represents an evolutionary balance between the functional conformer of alpha-synuclein (alpha-helix and/or random coil) and its pathogenic beta-sheet conformation. N-Terminal truncation of alpha-synuclein may promote pathogenesis.
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