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J Mol Biol. 2019 Nov 30. pii: S0022-2836(19)30679-5. doi: 10.1016/j.jmb.2019.11.014. [Epub ahead of print]

Structural Fuzziness of the RNA-Organizing Protein SERF Determines a Toxic Gain-of-interaction.

Author information

1
Division of Experimental Allergology and Immunodermatology, University of Oldenburg, Carl-von-Ossietzky-Straße 9-11, 26129 Oldenburg, Germany.
2
Christian Doppler Laboratory on Biotechnology of Skin Aging, Department of Biotechnology, BOKU - University of Natural Resources and Life Sciences Vienna, Muthgasse 18, 1190 Wien, Austria.
3
Institute of Pathophysiology and Immunology, Medical University of Graz, Heinrichstr. 31, 8010 Graz, Austria.
4
Department of Ophthalmology, Medical University of Graz, Auenbruggerplatz 4, 8036 Graz, Austria.
5
Institute of Applied Physiology, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany; Department of Medical Cell Biology, Institute of Anatomy and Cell Biology, University of Heidelberg, Im Neuenheimer Feld 307, 69120 Heidelberg, Germany.
6
Institute of Pharmaceutical Sciences, University of Graz, Schubertstr. 1, 8010 Graz, Austria.
7
Biotechnology Center of the TU Dresden, Tatzberg 47/49, 01307 Dresden, Germany.
8
Christian Doppler Laboratory on Biotechnology of Skin Aging, Department of Biotechnology, BOKU - University of Natural Resources and Life Sciences Vienna, Muthgasse 18, 1190 Wien, Austria; Ludwig Boltzmann Institute of Experimental and Clinical Traumatology, Donaueschingenstr. 13, 1200 Vienna, Austria; Austrian Cluster for Tissue Regeneration, Austria.
9
Institute of Chemistry, University of Graz, Heinrichstr. 28, 8010 Graz, Austria.
10
Institute of Pharmaceutical Sciences, University of Graz, Schubertstr. 1, 8010 Graz, Austria; Steiermärkische Krankenanstaltengesellschaft m.b.H. (KAGes), Stiftingtalstraße 4-6, 8010, Graz, Austria. Electronic address: fabio.falsone@uni-graz.at.

Abstract

The mechanisms by which protein complexes convert from functional to pathogenic are the subject of intensive research. Here, we report how functionally unfavorable protein interactions can be induced by structural fuzziness, i.e., by persisting conformational disorder in protein complexes. We show that extreme disorder in the bound state transforms the intrinsically disordered protein SERF1a from an RNA-organizing factor into a pathogenic enhancer of alpha-synuclein (aSyn) amyloid toxicity. We demonstrate that SERF1a promotes the incorporation of RNA into nucleoli and liquid-like artificial RNA-organelles by retaining an unusually high degree of conformational disorder in the RNA-bound state. However, this type of structural fuzziness also determines an undifferentiated interaction with aSyn. RNA and aSyn both bind to one identical, positively charged site of SERF1a by an analogous electrostatic binding mode, with similar binding affinities, and without any observable disorder-to-order transition. The absence of primary or secondary structure discriminants results in SERF1a being unable to select between nucleic acid and amyloidogenic protein, leading the pro-amyloid aSyn:SERF1a interaction to prevail in the cytosol under conditions of cellular stress. We suggest that fuzzy disorder in SERF1a complexes accounts for an adverse gain-of-interaction which favors toxic binding to aSyn at the expense of nontoxic RNA binding, thereby leading to a functionally distorted and pathogenic process. Thus, structural fuzziness constitutes a direct link between extreme conformational flexibility, amyloid aggregation, and the malfunctioning of RNA-associated cellular processes, three signatures of neurodegenerative proteinopathies.

KEYWORDS:

Alpha synuclein; Intrinsically disordered proteins; MOAG-4/SERF; RNA-binding; Structural fuzziness

PMID:
31794729
DOI:
10.1016/j.jmb.2019.11.014

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