Structural fuzziness of the RNA-organizing protein SERF determines a toxic gain-of-interaction.

07:00 EST 30th November 2019 | BioPortfolio

Summary of "Structural fuzziness of the RNA-organizing protein SERF determines a toxic gain-of-interaction."

The mechanisms by which protein complexes convert from functional into pathogenic are the subject of intensive research. Here, we report how functionally unfavourable 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 favours toxic binding to aSyn at the expense of non-toxic 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.


Journal Details

This article was published in the following journal.

Name: Journal of molecular biology
ISSN: 1089-8638


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