Structures of segments of ?-synuclein fused to maltose-binding protein suggest intermediate states during amyloid formation.

ABSTRACT: Aggregates of the protein ?-synuclein are the main component of Lewy bodies, the hallmark of Parkinson's disease. ?-Synuclein aggregates are also found in many human neurodegenerative diseases known as synucleinopathies. In vivo, ?-synuclein associates with membranes and adopts ?-helical conformations. The details of how ?-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 ?-synuclein. From crystal structures of fusions between MBP and four segments of ?-synuclein, we have been able to trace a virtual model of the first 72 residues of ?-synuclein. Instead of a mostly ?-helical conformation observed in the lipid environment, our crystal structures show ?-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 ?-synuclein can also form fiber-like nano-crystals or amyloid-like fibrils. Our structures suggest intermediate states during amyloid formation of ?-synuclein.

SUBMITTER: Zhao M 

PROVIDER: S-EPMC3104229 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature