Small-angle neutron scattering reveals the assembly of alpha-synuclein in lipid membranes

Divina Anunciado, Durgesh K. Rai, Shuo Qian, Volker Urban, Hugh O'Neill

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20 Scopus citations

Abstract

The aggregation of α-synuclein (asyn), an intrinsically disordered protein (IDP), is a hallmark in Parkinson's disease (PD). We investigated the conformational changes that asyn undergoes in the presence of membrane and membrane mimetics using small-angle neutron scattering (SANS). In solution, asyn is monomeric and unfolded assuming an ensemble of conformers spanning extended and compact conformations. Using the contrast variation technique and SANS, the protein scattering signal in the membrane-protein complexes is selectively highlighted in order to monitor its conformational changes in this environment. We showed that in the presence of phospholipid membranes asyn transitions from a monodisperse state to aggregated structures with sizes ranging from 200 to 900 Å coexisting with the monomeric species. Detailed SANS data analysis revealed that asyn aggregates have a hierarchical organization in which clusters of smaller asyn aggregates assemble to form the larger structures. This study provides new insight into the mechanism of asyn aggregation. We propose an aggregation mechanism in which stable asyn aggregates seed the aggregation process and hence the hierarchical assembly of structures. Our findings demonstrate that membrane-induced conformational changes in asyn lead to its heterogeneous aggregation which could be physiologically relevant in its function or in the diseased state.

Original languageEnglish
Pages (from-to)1881-1889
Number of pages9
JournalBiochimica et Biophysica Acta - Proteins and Proteomics
Volume1854
Issue number12
DOIs
StatePublished - Dec 1 2015

Funding

This manuscript has been authored by UT-Battelle, LLC under Contract No. DE-AC05-00OR22725 with the U.S. Department of Energy. The United States Government retains and the publisher, by accepting the article for publication, acknowledges that the United States Government retains a non-exclusive, paid-up, irrevocable, world-wide license to publish or reproduce the published form of this manuscript, or allow others to do so, for United States Government purposes. The Department of Energy will provide public access to these results of federally sponsored research in accordance with the DOE Public Access Plan ( http://energy.gov/downloads/doe-public-access-plan ). The authors would like to thank Dr. Dung Vu of Los Alamos National Laboratory for the asyn plasmid. We also thank Dr. Sai Venkatish Pingali for his valuable discussions on SANS data analysis. The Center for Structural Molecular Biology supports the Bio-SANS instrument and laboratories used for this research. It is funded by the Office of Biological and Environmental Research of the U.S. Department of Energy . The High Flux Isotope Reactor is sponsored by the Scientific User Facilities Division, Office of Basic Energy Sciences, U.S. Department of Energy . Oak Ridge National Laboratory is managed by UT-Battelle, LLC, for the U. S. DOE under Contract No. DE-AC05-00OR22725.

Keywords

  • Aggregation
  • Alpha-synuclein
  • Hierarchical structure
  • Lipid membrane
  • Parkinson's disease
  • Small-angle scattering

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