Biology subjects

Zangger, K.

Publications and source records attributed to Zangger, K..

2 recordsLinked to original sources

bioRxiv2023

Vibrio cholerae's ToxRS Bile Sensing System

Cholera represents a diarrheal disease caused by the Gram-negative bacterium Vibrio cholerae. Its environmental persistence causing recurring sudden outbreaks is enabled by V. choleraes rapid adaption to changing environments involving sensory proteins like ToxR and ToxS. Located at the inner membrane, ToxR and ToxS react to environmental stimuli like bile acid, thereby inducing survival strategies e.g. bile resistance and virulence regulation. Currently, transcription factor ToxR is described as main environmental sensor for bile acid, whose activity is enhanced by binding to ToxS. Here, the presented crystal structure of the sensory domains of ToxR and ToxS in combination with multiple bile acid interaction studies, reveals that a bile binding pocket of ToxS is only properly folded upon binding to ToxR. These findings support the previously suggested link between ToxRS and VtrAC-like co-component systems. Besides VtrAC, ToxRS is now the only experimentally determined structure within this recently defined superfamily, further emphasizing its significance. In-depth analysis of the ToxRS complex reveals its remarkable conservation across various Vibrio species, underlining the significance of conserved residues in the ToxS barrel and the more diverse ToxR sensory domain. Unraveling the intricate mechanisms governing ToxRSs environmental sensing capabilities, provides a promising tool for disruption of this vital interaction, ultimately inhibiting Vibrios survival and virulence. Our findings hold far-reaching implications for all Vibrio strains that rely on the ToxRS system as a shared sensory cornerstone for adapting to their surroundings.

biochemistry↗

bioRxiv2019

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

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 RNA-organelles, 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.

biochemistry↗