Structure and Dynamics of Micelle-bound Human α-Synuclein

• Published in: The Journal of biological chemistry 2005-03, Vol.280 (10), p.9595-9603
• Main Authors: Ulmer, Tobias S., Bax, Ad, Cole, Nelson B., Nussbaum, Robert L.
• Format: Article
• Language: English
• Subjects: alpha-Synuclein; Amino Acid Sequence; Binding Sites; Detergents; Humans; Magnetic Resonance Spectroscopy; Micelles; Models, Molecular; Molecular Sequence Data; Nerve Tissue Proteins - chemistry; Phosphoproteins - chemistry; Protein Structure, Secondary; Sodium Dodecyl Sulfate; Synucleins
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M411805200

Misfolding of the protein α-synuclein (aS), which associates with presynaptic vesicles, has been implicated in the molecular chain of events leading to Parkinson's disease. Here, the structure and dynamics of micelle-bound aS are reported. Val3-Val37 and Lys45-Thr92 form curved α-helices, connected by a well ordered, extended linker in an unexpected anti-parallel arrangement, followed by another short extended region (Gly93-Lys97), overlapping the recently identified chaperone-mediated autophagy recognition motif and a highly mobile tail (Asp98-Ala140). Helix curvature is significantly less than predicted based on the native micelle shape, indicating a deformation of the micelle by aS. Structural and dynamic parameters show a reduced helical content for Ala30-Val37. A dynamic variation in interhelical distance on the microsecond timescale is complemented by enhanced sub-nanosecond timescale dynamics, particularly in the remarkably glycine-rich segments of the helices. These unusually rich dynamics may serve to mitigate the effect of aS binding on membrane fluidity. The well ordered conformation of the helix-helix connector indicates a defined interaction with lipidic surfaces, suggesting that, when bound to larger diameter synaptic vesicles, it can act as a switch between this structure and a previously proposed uninterrupted helix.