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DNP-Enhanced MAS NMR: A Tool to Snapshot Conformational Ensembles of α-Synuclein in Different States

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  • Boran Uluca, Heinrich Heine University Düsseldorf
  • ,
  • Thibault Viennet
  • Dušan Petrović, Heinrich Heine University Düsseldorf
  • ,
  • Hamed Shaykhalishahi, Heinrich Heine University Düsseldorf
  • ,
  • Franziska Weirich, Heinrich Heine University Düsseldorf
  • ,
  • Ayşenur Gönülalan, Heinrich Heine University Düsseldorf
  • ,
  • Birgit Strodel, Heinrich Heine University Düsseldorf
  • ,
  • Manuel Etzkorn, Heinrich Heine University Düsseldorf
  • ,
  • Wolfgang Hoyer, Heinrich Heine University Düsseldorf
  • ,
  • Henrike Heise, Heinrich Heine University Düsseldorf

Intrinsically disordered proteins dynamically sample a wide conformational space and therefore do not adopt a stable and defined three-dimensional conformation. The structural heterogeneity is related to their proper functioning in physiological processes. Knowledge of the conformational ensemble is crucial for a complete comprehension of this kind of proteins. We here present an approach that utilizes dynamic nuclear polarization-enhanced solid-state NMR spectroscopy of sparsely isotope-labeled proteins in frozen solution to take snapshots of the complete structural ensembles by exploiting the inhomogeneously broadened line-shapes. We investigated the intrinsically disordered protein α-synuclein (α-syn), which plays a key role in the etiology of Parkinson's disease, in three different physiologically relevant states. For the free monomer in frozen solution we could see that the so-called “random coil conformation” consists of α-helical and β-sheet-like conformations, and that secondary chemical shifts of neighboring amino acids tend to be correlated, indicative of frequent formation of secondary structure elements. Based on these results, we could estimate the number of disordered regions in fibrillar α-syn as well as in α-syn bound to membranes in different protein-to-lipid ratios. Our approach thus provides quantitative information on the propensity to sample transient secondary structures in different functional states. Molecular dynamics simulations rationalize the results.

Original languageEnglish
JournalBiophysical Journal
Pages (from-to)1614-1623
Number of pages10
Publication statusPublished - 10 Apr 2018
Externally publishedYes

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