期刊
PROTEIN SCIENCE
卷 20, 期 6, 页码 996-1004出版社
WILEY
DOI: 10.1002/pro.630
关键词
alpha-synuclein; amyloid; fibrillation; intermediate; MBP fusion; nano-crystal; X-ray crystallography
资金
- NIH
- NSF
- DOE
- Direct For Biological Sciences [0958111] Funding Source: National Science Foundation
- Div Of Molecular and Cellular Bioscience [0958111] Funding Source: National Science Foundation
Aggregates of the protein alpha-synuclein are the main component of Lewy bodies, the hallmark of Parkinson's disease. alpha-Synuclein aggregates are also found in many human neurodegenerative diseases known as synucleinopathies. In vivo, alpha-synuclein associates with membranes and adopts alpha-helical conformations. The details of how alpha-synuclein converts from the functional native state to amyloid aggregates remain unknown. In this study, we use maltose-binding protein (MBP) as a carrier to crystallize segments of alpha-synuclein. From crystal structures of fusions between MBP and four segments of alpha-synuclein, we have been able to trace a virtual model of the first 72 residues of alpha-synuclein. Instead of a mostly alpha-helical conformation observed in the lipid environment, our crystal structures show alpha-helices only at residues 1-13 and 20-34. The remaining segments are extended loops or coils. All of the predicted fiber-forming segments based on the 3D profile method are in extended conformations. We further show that the MBP fusion proteins with fiber-forming segments from alpha-synuclein can also form fiber-like nano-crystals or amyloid-like fibrils. Our structures suggest intermediate states during amyloid formation of alpha-synuclein.
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