Structures of segments of α‐synuclein fused to maltose‐binding protein suggest intermediate states during amyloid formation

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