Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 280, Issue 52, Pages 43179-43187Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M507624200
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- Intramural NIH HHS Funding Source: Medline
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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 (Val(26)-Ala(29)) 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.
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