Structural fuzziness of the RNA-organizing protein SERF1a determines a toxic gain-of-interaction

Abstract

Members of the MOAG/SERF protein family have been attributed a neuropathologic significance because of their ability to enhance the proteotoxic polymerization of amyloidogenic proteins such as alpha-Synuclein (aSyn). However, the cellular function remains unknown. Here, we identify SERF1a as an RNA-organizing protein i) with no structural homology to canonical RNA-binding proteins, ii) with an RNA-chaperoning activity which favours the incorporation of RNA into nucleoli and liquid-like artificial RNAorganelles, and iii) with a high degree of conformational disorder in the RNA-bound state. We demonstrate that this type of structural fuzziness determines an undifferentiated interaction of SERF1a with aSyn and RNA. Both molecules 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 distinguish between nucleic acid and amyloidogenic protein, leading the pro-amyloid aSyn:SERF1a interaction to prevail under conditions of cellular stress. We suggest that structural fuzziness of SERF1a accounts for an adverse gain-of-interaction which favours toxic binding to aSyn at the expense of non-toxic RNA binding, therefore promoting a functionally distorted and pathogenic process. Our results provide a direct link between structural disorder, amyloid aggregation and the malfunctioning of RNA-associated cellular processes, three hallmarks of neurodegenerative diseases.Similarly, the probe Cy5-R21(+) failed to target isolated nucleoli as a monomer (Fig. 5D) or

SERF deletion modifies amyloid aggregation in a mouse model of Alzheimer’s disease

“…However, under stress conditions, it was shown to migrate to the cytoplasm, where it could drive amyloid toxicity. 88 While there was no compensatory upregulation of SERF1 in response to SERF2 KO and a similar mode of action remains to be demonstrated for SERF2, the structural (which was not certified by peer review) is the author/funder. All rights reserved.…”

“…The copyright holder for this preprint this version posted January 5, 2021. ; https://doi.org/10.1101/2021.01.05.423442 doi: bioRxiv preprint SERF1A through a region which is highly conserved in MOAG-4 and SERF2 86 . In this study, we have demonstrated in cells and mice that SERF2 provides a growth advantage during development.…”

“…Previous studies identified MOAG-4 and its human orthologs SERF1A and SERF2 and their potential to modify the aggregation of amyloidogenic proteins. While the exact endogenous biological function of these peptides remains unclear, a recent study has provided evidence for RNA-binding properties of SERF1A through a region which is highly conserved in MOAG-4 and SERF2(Meyer et al , 2019). In this study, we have demonstrated in cells and mice that SERF2 provides a growth advantage during development.…”

Regulation of Age-Related Protein Toxicity

“…Electrostatic interactions between MOAG-4/SERF1a and alpha-synuclein accelerate the formation of alpha-synuclein fibrils ( Falsone et al, 2012 ; Yoshimura et al, 2017 ; Merle et al, 2019 ). This aggregation-promoting effect of SERF on alpha-synuclein was recently suggested to be a toxic side effect, mediated by an interaction between SERF1a and the negatively charged C-terminus of alpha-synuclein ( Meyer et al, 2019 ). This study suggested that SERF1a acts as an RNA chaperone in the formation of liquid-like RNA organelles.…”

“…This study suggested that SERF1a acts as an RNA chaperone in the formation of liquid-like RNA organelles. Under stressful conditions, RNA and alpha-synuclein may compete for SERF binding, possibly favoring an interaction between alpha-synuclein and SERF that accelerates amyloid formation ( Meyer et al, 2019 ). Such stressful conditions could arise during aging as protein homeostasis declines.…”