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Predicting protein condensation from sequence: new and widespread roles for condensates in physiology and disease

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SPLW03 - Biological condensates: cellular mechanisms governed by phase transitions

In the last decade it has become increasingly clear that biomolecular condensates are widespread within cells. Besides membranebound compartments, these assemblies constitute a powerful and versatile way for the cell to compartmentalize and orchestrate its internal biochemistry. While the number of validated scaffold and client proteins has steadily grown, how this behavior is actually encoded in sequence remains understudied. Since transmembrane domains can be pretty accurately predicted from sequence, similar efforts have been explored for condensate proteins. Most of the current prediction tools unfortunately rely on the available in vitro data for condensation. As the field initially focused on prion-like domains, the resulting predictions are often biased towards such sequences. Many condensates do not rely on such prion-like domains though, but typically come in different flavors of their chemical space. Here we leveraged a simple paradigm of complex coacervation to probe such additional chemistries. Using ex vivo enrichment strategies coupled to mass spectrometry-based proteomics, we unbiasedly uncover a whole new set of candidate condensate proteins. Training a machine learning algorithm on this dataset allows us to predict such behavior with surprising accuracy from sequence. This approach allowed us to uncover a whole new set of uncharacterized condensate proteins with essential functions to human cells. Additionally, our algorithm predicts that condensation behavior is pervasive—not only within—but also outside of cells. We unexpectedly uncover novel and evolutionary conserved roles for condensation in animal physiology, ranging from innate immune and venom systems to biomaterials and biofluids. Several of these protein classes and their condensation-driving features are rapidly evolving, arguing that phase separation is not merely an epiphenomenon but a core functional mechanism under direct selective pressure. 

This talk is part of the Isaac Newton Institute Seminar Series series.

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