title: Comparison of structure and dynamics of micelle-bound human alpha-synuclein and Parkinson disease variants.
abstract: Three point mutations (A30P, E46K, and A53T) as well as gene triplication genetically link the 140-residue protein alpha-synuclein (aS) to the development of Parkinson disease. Here, the structure and dynamics of micelle-bound aS(A30P) and aS(A53T) are described and compared with wild-type aS, in addition to describing the aS-micelle interaction. A53T is sensed only by directly adjacent residues and leaves the backbone structure and dynamics indistinguishable from the wild type. A30P interrupts one helix turn (Val26-Ala29) and destabilizes the preceding one. A shift in helix register following A30P disturbs the canonical succession of polar and hydrophobic residues for at least two turns. The shortened helix-N adopts a slightly higher helical content and is less bent, indicating that strain was present in the micelle-bound helix. In the vicinity of the A30P-induced perturbations, the underlying micelle environment has rearranged, but nevertheless all aS variants maintain similar interrelationships with the micelle. Moreover, aS-micelle immersion correlates well with fast and slow aS backbone dynamics, allowing a rare insight into protein-micelle interplay.
authors.affiliation: Laboratory of Chemical Physics, NIDDK, National Institutes of Health, Bethesda, Maryland 20892, USA. tulmer@usc.edu
authors.forename: Tobias S
authors.initials: TS
authors.lastname: Ulmer
authors.forename: Ad
authors.initials: A
authors.lastname: Bax
mesh_terms: D000409:Alanine / Q000737:chemistry; D000595:Amino Acid Sequence; D006801:Humans; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008823:Micelles; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics / Q000473:pathology*; D017354:Point Mutation; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012694:Serine / Q000737:chemistry; D012967:Sodium Dodecyl Sulfate / Q000737:chemistry; D014633:Valine / Q000737:chemistry; D051844:alpha-Synuclein / Q000737:chemistry*
chemical_list: D008823:Micelles; D051844:alpha-Synuclein; D012967:Sodium Dodecyl Sulfate; D012694:Serine; D014633:Valine; D000409:Alanine