Applied Magnetic Resonance

, Volume 46, Issue 4, pp 369–388 | Cite as

Three Long-Range Distance Constraints and an Approach Towards a Model for the α-Synuclein-Fibril Fold

  • Maryam Hashemi Shabestari
  • Pravin Kumar
  • Ine M. J. Segers-Nolten
  • Mireille M. A. E. Claessens
  • Bart D. van Rooijen
  • Vinod Subramaniam
  • Martina Huber
Article
  • 216 Downloads

Abstract

Amyloid fibrils and plaques are the hallmark of neurodegenerative diseases. In Parkinson’s disease, plaques (Lewy bodies) consist predominantly of the α-synuclein (αS) protein. To understand aggregation, the molecular architecture of αS fibrils needs to be known. Here, we determine nm-distance constraints for the protein in the fibril by double electron–electron paramagnetic resonance (DEER) on doubly spin-labeled αS variants, diamagnetically diluted with wild-type αS to suppress intermolecular interactions. Intramolecular distances in three pairs (56/69, 56/90 and 69/90) are reported. An approach to derive a model for the fibril fold from sparse distance data assuming only parallel β-sheets is described. Using the distances obtained in this study as input, a model is obtained with three strands, comprising residues 56–90, in which the strands consist of 8–12 residues each. Limitations of the approach are discussed in detail, showing that the interpretation of the data does not yet yield an unambiguous structure model. Possible avenues to improve this situation are described.

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Copyright information

© Springer-Verlag Wien 2015

Authors and Affiliations

  • Maryam Hashemi Shabestari
    • 1
  • Pravin Kumar
    • 1
  • Ine M. J. Segers-Nolten
    • 2
  • Mireille M. A. E. Claessens
    • 2
  • Bart D. van Rooijen
    • 2
    • 4
  • Vinod Subramaniam
    • 2
    • 3
  • Martina Huber
    • 1
  1. 1.Huygens-Kammerlingh-Onnes Laboratory, Department of PhysicsLeiden UniversityLeidenThe Netherlands
  2. 2.Nanobiophysics, MESA + Institute for NanotechnologyUniversity of TwenteEnschedeThe Netherlands
  3. 3.MIRA Institute for Biomedical Technology and Technical MedicineUniversity of Twente, and FOM Institute AMOLFAmsterdamThe Netherlands
  4. 4.Department of RadiologyMaastricht University Medical CenterMaastrichtThe Netherlands

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