期刊
BIOCHEMISTRY
卷 44, 期 16, 页码 6003-6014出版社
AMER CHEMICAL SOC
DOI: 10.1021/bi0474867
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资金
- NIGMS NIH HHS [T32 GM07183, 5 T32 GM07281] Funding Source: Medline
- NINDS NIH HHS [R01 NS042852] Funding Source: Medline
Recent solid-state NMR data (1) demonstrate that A beta(1-40) adopts a conformation in amyloid fibrils with two in-register, parallel P-sheets, connected by a bend structure encompassing residues D(23)VGSNKG(29), with a close contact between the side chains of Asp23 and Lys28. We hypothesized that forming this bend structure might be rate-limiting in fibril formation, as indicated by the lag period typically observed in the kinetics of A beta(1-40) fibrillogenesis. We synthesized A beta(1-40)-Lactam(D23/K28), a congener A beta(1-40) peptide that contains a lactam bridge between the side chains of Asp23 and Lys28. A beta(1-40)-Lactam(D23/K28) forms fibrils similar to those formed by A beta(1-40). The kinetics of fibrillogenesis, however, occur without the typical lag period, and at a rate; approximate to 1000-fold greater than is seen with A beta(1-40) fibrillogenesis. The strong tendency toward self-association is also shown by size exclusion chromatography in which A beta(1-40)-Lactam(D23/K28) forms oligomers even at concentrations of approximate to 1-5 mu M. Under the same conditions, A beta(1-40) shows no detectable oligomers by size exclusion chromatography. Our data suggest that A beta(1-40)-Lactam(D23/K28) could bypass an unfavorable folding step in fibrillogenesis, because the lactam linkage preforms a bendlike structure in the peptide. Consistent with this view A beta(1-40) growth is efficiently nucleated by A beta(1-40)-Lactam(D23/K28) fibril seeds.
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