Predictive atomic resolution descriptions of intrinsically disordered hTau40 and α-synuclein in solution from NMR and small angle scattering

Martin Schwalbe, Valéry Ozenne, Stefan Bibow, Mariusz Jaremko, Lukasz Jaremko, Michal Gajda, Malene Ringkjøbing Jensen, Jacek Biernat, Stefan Becker, Eckhard Mandelkow, Markus Zweckstetter*, Martin Blackledge

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

153 Scopus citations

Abstract

The development of molecular descriptions of intrinsically disordered proteins (IDPs) is essential for elucidating conformational transitions that characterize common neurodegenerative disorders. We use nuclear magnetic resonance, small angle scattering, and molecular ensemble approaches to characterize the IDPs Tau and α-synuclein. Ensemble descriptions of IDPs are highly underdetermined due to the inherently large number of degrees of conformational freedom compared with available experimental measurements. Using extensive cross-validation we show that five different types of independent experimental parameters are predicted more accurately by selected ensembles than by statistical coil descriptions. The improvement increases in regions whose local sampling deviates from statistical coil, validating the derived conformational description. Using these approaches we identify enhanced polyproline II sampling in aggregation-nucleation sites, supporting suggestions that this region of conformational space is important for aggregation.

Original languageEnglish (US)
Pages (from-to)238-249
Number of pages12
JournalStructure
Volume22
Issue number2
DOIs
StatePublished - Feb 4 2014
Externally publishedYes

Bibliographical note

Funding Information:
We thank Ilka Lindner for preparation of Tau samples. This work was supported financially by ANR Protein Disorder (JCJC 2010 to M.R.J.), TAUSTRUCT (MALZ 2010 to M.B.), Deutsche Forschungsgemeinschaft (71/7-1 to M.Z.), START and Ventures Programmes of Foundation for Polish Science (Fundacja na rzecz Nauki Polskiej; http://www.fnp.org.pl/ ) operated within the Innovative Economy Operational Programme (IE OP) 2007-2013 within European Regional Development Fund (to L.J. and M.J.), and the Iuventus Plus project IP2011 019471 from the Polish Ministry of Sciences and Higher Education (to M.J.).

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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