Disordered Motifs and Domains in Cell Control - October 11-15, 2014

Disordered Motifs and Domains in Cell Control

Poster Session I

23-POS Board 23 Chaperoning of Aggregation Prone Stretches Luca Ferrari 1 , Magdalena Wawrzyniuk 1 , G. Elif Karagöz 1,2 , Madelon M. Maurice 3 , Stefan G. Rüdiger 1 . 1 Utrecht University, Utrecht, Netherlands, 2 UCSF, San Francisco, CA, USA, 3 UMC Utrecht, Utrecht, Netherlands. Protein aggregation is a common landmark of many human diseases, yet its molecular basis remains poorly understood. The aggregation-prone stretches involved in this process are usually present buried within folded domain or otherwise buffered by the cellular environment. Mutations can either expose buried stretches or introduce new aggregation-prone sites, as observed for cancers involving tumor suppressors in signaling pathways. We recently characterized the interaction between the molecular chaperone Hsp90 and the aggregation prone stretches of Tau, an intrinsically disordered protein involved in Alzheimer’s disease (Karagöz et al., Cell 2014). The described interaction together with the importance of Hsp90 in late folding events suggest a pivotal role of this chaperone in the aggregation prone stretches dynamics. The aim of our study is to understand how these dynamics occurs in folded proteins, folding intermediates and intrinsically disordered substrates. To address this question we applied fluorescence techniques. We selectively labelled the Hsp90 binding region of Tau to unravel how this chaperone alters aggregation kinetics. The role of co- chaperones and ATP cycle were taken into account. We turned to intrinsically disordered, aggregation-prone tumor suppressors, to test whether the paradigms gained from our study also apply to other molecular processes. We analyzed analysed Hsp90 interactions with members of the Wnt signalling cascade that are destabilized by cancer mutants. Indeed we found that cancer mutations in the destruction complex of the Wnt cascade cause protein aggregation and as a result tumour growth. The aggregation phenotype correlates with changes in the interactome, suggesting a causal link between aggregation and cancer phenotype. Our study provides insights into molecular basis of protein aggregation and its deleterious effects on cellular activities. Our results shed also light on the counter intuitive concept of the interaction between intrinsically disordered proteins and the folding machinery of the cell.

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