On July 1st, SFB1551 had the pleasure of hosting a double lecture featuring guest speakers Tanja Mittag and Kresten Lindorff-Larsen. The event was well-attended, with a full house eagerly awaiting Tanja’s presentation on “Driving Forces for Phase Separation, Material Properties, and Aging Processes of Condensates.” Tanja began by introducing phase separation as a fundamental principle underlying the spatial organization and functional specialization of cellular components. Tanja explained its role in forming and maintaining structures such as heterochromatin, super enhancers, RNA-mediated processes, and membrane domains, thus influencing cellular architecture and dynamics. Tanja emphasized the importance of the interplay between intrinsically disordered regions, stickers, and spacers in phase separation. Specifically, she discussed how aromatic residues can impact compaction and drive phase separation, and how changes in viscoelastic properties can lead to various pathologies by disrupting normal cellular processes, promoting toxic aggregate formation, and impairing dynamic responses to cellular signals. Tanja then focused on stress granules (SGs) and their involvement in the pathogenesis of neurodegenerative and neuromuscular disorders collectively known as multisystem proteinopathy (MSP), including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Her research suggests that prolonged SG assembly can contribute to disease, particularly through mutations in RNA-binding proteins that promote fibril formation. She highlighted how the aging of SGs, including their transition from condensates to fibrils and subsequent dynamical arrest, may drive pathogenesis. However, she also noted that SGs might play a role in slowing down the fibril formation of proteins like TDP-43.
After a short coffee break, Kresten captivated the audience with his talk entitled “Towards Structure Prediction and Design of Disordered Proteins.” His research focuses on studying protein dynamics and their relationship to protein structure and function by integrating computational methods with experimental studies. Kresten detailed the development of a liquid-liquid phase behavior model for intrinsically disordered proteins (IDPs). This model, based on hydrophobicity scales for quantifying amino acid hydrophobicity, was optimized using data from SAXS and Pre-NMR and automated via a Bayesian parameter learning procedure until simulations accurately reflected the experimental data of the training set. The resulting model, named “CALVADOS” (Coarse-grained Approach to LLPS), effectively predicts the propensity of diverse proteins to undergo liquid-liquid phase separation. Kresten further described how they have generated conformational ensembles of all intrinsically disordered regions of the human proteome, using these ensembles to provide insights into sequence-ensemble relationships and the evolutionary conservation of IDR properties. In conclusion, the advanced models of protein folding and evolution developed through Kresten’s research not only enhance our understanding of protein behavior but also hold significant potential for unraveling the mechanisms of disease development, paving the way for novel therapeutic strategies.
This double lecture series concluded with a delightful barbecue, providing a perfect opportunity for our guest speakers and attendees to interact and network in a relaxed and enjoyable setting.
