2. Academic Validation
  3. Increased Aggregation Tendency of Alpha-Synuclein in a Fully Disordered Protein Complex

Increased Aggregation Tendency of Alpha-Synuclein in a Fully Disordered Protein Complex

  • J Mol Biol. 2019 Jun 28;431(14):2581-2598. doi: 10.1016/j.jmb.2019.04.031.
David A Merle 1,  Anja Witternigg 1,  Carmen Tam-Amersdorfer 2,  Christoph Hartlmüller 3,  Emil Spreitzer 4,  Evelyne Schrank 1,  Sabine Wagner-Lichtenegger 5,  Oliver Werzer 6,  Klaus Zangger 1,  Andreas J Kungl 6,  Tobias Madl 7,  N Helge Meyer 8,  S Fabio Falsone 9
Affiliations

Affiliations

  • 1 Institute of Chemistry, University of Graz, Heinrichstr. 28, 8010 Graz, Austria.
  • 2 Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Institute of Pathophysiology and Immunology, Medical University of Graz, Heinrichstr, 31, 8010 Graz, Austria.
  • 3 Center for Integrated Protein Science Munich (CIPSM) at the Department of Chemistry Technische Universität München, Lichtenbergstr. 4, 87548, Garching, Germany; Institute of Structural Biology, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.
  • 4 Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Institute of Molecular Biology & Biochemistry, Medical University of Graz, Neue Stiftingtalstrasse 6, 8010 Graz, Austria.
  • 5 Diagnostic & Research Center for Molecular BioMedicine, Institute of Hygiene, Microbiology and Environmental Medicine, Medical University Graz, Neue Stiftingtalstraße 2, 8010 Graz, Austria.
  • 6 Institute of Pharmaceutical Sciences, University of Graz, Schubertstr. 1, 8010 Graz, Austria.
  • 7 Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Institute of Molecular Biology & Biochemistry, Medical University of Graz, Neue Stiftingtalstrasse 6, 8010 Graz, Austria. Electronic address: [email protected].
  • 8 Division of Experimental Allergology and Immunodermatology, Department of Human Medicine, University of Oldenburg, Carl-von-Ossietzky-Straße 9-11, 26129 Oldenburg, Germany. Electronic address: [email protected].
  • 9 Institute of Pharmaceutical Sciences, University of Graz, Schubertstr. 1, 8010 Graz, Austria. Electronic address: [email protected].
PMID: 31034892 DOI: 10.1016/j.jmb.2019.04.031
Abstract

The recent discovery of biologically active fully disordered, so called random fuzzy protein-protein interactions leads to the question of how the high flexibility of these protein complexes correlates to aggregation and pathologic misfolding. We identify the structural mechanism by which a random fuzzy protein complex composed of the intrinsically disordered proteins alpha-Synuclein and SERF1a is able to potentiate cytotoxic aggregation. A structural model derived from an integrated NMR/SAXS analysis of the reconstituted aSyn:SERF1a complex enabled us to observe the partial deprotection of one precise aSyn amyloid nucleation element in the fully unstructured ensemble. This minimal exposure was sufficient to increase the amyloidogenic tendency of SERF1a-bound aSyn. Our findings provide a structural explanation of the previously observed pro-amyloid activity of SERF1a. They further demonstrate that random fuzziness can trigger a structurally organized disease-associated reaction such as amyloid polymerization.

Keywords

Alpha synuclein; Amyloids; Fuzzy complexes; Intrinsically disordered proteins; MOAG-4/SERF.

Figures