期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 141, 期 1, 页码 363-369出版社
AMER CHEMICAL SOC
DOI: 10.1021/jacs.8b10289
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资金
- National Institute of General Medical Sciences from the National Institutes of Health [P41 GM103403]
- NIH-ORIP HEI grant [S10OD021527]
- DOE Office of Science [DE-AC02-06CH11357]
- NSF [DMR-1506886]
- University of Texas at El Paso
- Israeli Science Foundation [550/15]
- European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program [BISON-694426]
- Tel Aviv University
The ensemble of native, folded state was once considered to represent the global energy minimum of a given protein sequence. More recently, the discovery of the cross-beta amyloid state revealed that deeper energy minima exist, often associated with pathogenic, fibrillar deposits, when the concentration of proteins reaches a critical value. Fortunately, a sizable energy barrier impedes the conversion from native to pathogenic states. However, little is known about the structure of the related transition state. In addition, there are indications of polymorphism in the amyloidogenic process. Here, we report the first evidence of the conversion of metastable cross alpha-helical crystals to thermodynamically stable cross-beta-sheet-like fibrils by a de novo designed heptapeptide. Furthermore, for the first time, we demonstrate at atomic resolution that the flip of a peptide plane from a type I to a type II' turn facilitates transformation to cross-beta structure and assembly of a dry steric zipper. This study establishes the potential of a peptide turn, a common protein secondary structure, to serve as a principal gatekeeper between a native metastable folded state and the amyloid state.
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