An intersheet packing interaction in A beta fibrils mapped by disulfide cross-linking.
An intersheet packing interaction in A beta fibrils mapped by disulfide cross-linking.
复制标题
通过二硫键交联绘制 A β 原纤维中的片间堆积相互作用。
DOI：
10.1021/bi048019s
复制
发表时间：
2004
期刊：
影响因子：
--
通讯作者：
Wetzel,Ronald
中科院分区：
文献类型：
--
作者：
Shivaprasad,Shankaramma;Wetzel,Ronald
Most models for the central cross-β folding unit in amyloid fibrils of the Alzheimer's plaque protein Aβ align the peptides in register in H-bonded, parallel β-sheet structure. Some models require the Aβ peptide to undergo a chain reversal when folding into the amyloid core, while other models feature very long extended chains, or zigzag chains, traversing the protofilament. In this paper we introduce the use of disulfide bond cross-linking to probe the fold within the core and the packing interactions between β-sheets. In one approach, amyloid fibrils grown under reducing conditions from each of three double cysteine mutants (17/34, 17/35, and 17/36) of the Aβ(1−40) sequence were subjected to oxidizing conditions. Of these three mutants, only the Leu17Cys/Leu34Cys peptide could be cross-linked efficiently while resident in fibrils. In another approach, double Cys mutants were cross-linked as monomers before aggregation, and the resulting fibrils were assessed for stability, antibody binding, dye binding, and cross-seeding efficiency. Here too, fibrils from the 17/34 double Cys mutant most closely resemble wild-type Aβ(1−40) fibrils. These data support models of the Aβ fibril in which the Leu17 and Leu34 side chains of the same peptide pack against each other at the β-sheet interface within the amyloid core. Related cross-linking strategies may reveal longer range spatial relationships. The ability of the cross-linked 17/35 double Cys mutant Aβ to also make amyloid fibrils illustrates a remarkable plasticity of the amyloid structure and suggests a structural mechanism for the generation of conformational variants of amyloid.
