Complex cellular landscapes of proteins include the dense, liquid-like droplet state and the solid-like amyloid state, in addition to the native state. The amyloid state, which is often pathological, can be formed through the deposition pathway from the native state and through the condensation pathway from the droplet state. I present a uniform framework to describe both pathways and identify mutations biasing towards these aggregation mechanisms. The droplet landscape model is a sequence-based, generic approach that simultaneously estimates the probability of droplet formation and the likelihood of state conversion. The method exploits that the interactions driving the droplet state sample disordered binding modes, whereas those governing the amyloid state sample ordered binding modes, which can simultaneously be estimated from sequence without information on the interaction partners. In addition, we predict the multiplicity of binding modes, that a given protein region can sample under different cellular conditions. I will demonstrate the application of the droplet landscape approach to both pathological and functional aggregates, in particular predicting mutations associated with amyotrophic lateral sclerosis and those facilitating muscle lineage development.
References
M. Vendruscolo, M Fuxreiter (2022) Protein Condensation Diseases: Therapeutic Opportunities. Nat Commun 13, 5500, doi: 10.1038/s41467-022-32940-7
Hatos A, Tosatto SCE, Vendruscolo M, Fuxreiter M. (2022) FuzDrop on AlphaFold: visualizing the sequence-dependent propensity of liquid-liquid phase separation and aggregation of proteins. Nucleic Acids Res. 50(W1), W337-44
Gönczi M., Teixeira JMC, Barrera-Vilarmau S., Mediani L. , Antoniani F. , Nagy TM, Fehér K., Ráduly Z., Ambrus V., Tőzsér J., Barta E., Kövér KE., Csernoch L., Carra S. , Fuxreiter M. (2023) Alternatively spliced exon regulates context-dependent MEF2D higher-order assembly during myogenesis Nature Communications 14, 1329.
Horvath A, Vendruscolo M, Fuxreiter M. (2022) Sequence-based Prediction of the Cellular Toxicity Associated with Amyloid Aggregation within Protein Condensates Biochemistry 61, 2461-2469.