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Unconventional phosphorylation-tuned motifs for protein function under the lens of structural biology

The Carlsberg Foundation Distinguished Fellowships

What

We aim at providing a framework which allows a robust characterization of unconventional functional motifs for protein-protein interactions in intrinsically disordered proteins. In particular, we are interested in those functional motifs which resemble already known ones but that are much more degenerated and thus elude bioinformatic algorithms. They are often tuned by post-translational modifications, such as phosphorylation, which add an extra layer of complexity to their investigation.

Why

Our project will provide a general and robust workflow that can be in principle also extended to canonical motifs for a more profound understanding of the related molecular mechanisms. The asset will be the possibility to finally unveil entirely new classes of short linear interacting motifs that have been challenging the current bioinformatic approaches and understand the related mode of action. This knowledge is fundamental for applicative purposes, i.e., for industrial or pharmaceutical applications of modified variants of the disordered peptides embedding the motifs under investigation.

How

We will implement an integrative approach where we will bring together the results from structure-based free energy calculations on protein structural ensembles, molecular dynamics simulations, in-vitro assays based on peptide arrays and NMR experiments. Moreover, thanks to the tight collaboration with cellular biologists at our institute we will exploit cellular models to test the most promising interactions in a cellular context and finally link their structural properties to the phenotype.

SSR

The understanding of the underlying mechanisms of protein-protein interactions triggered by disordered protein regions that are modulated by post-translational modifications is fundamental for more transformative purposes. On a longer-term framework, the knowledge generated by this project will have the potential to be exploited at different levels, such as for the design of peptide mimetics or bioactive peptides which can be used for industrial purposes, or even to develop new assays by coupling peptides with signal reporters for protein quantification.