How do proteins interact in the cellular environment? Are the concepts, which have been developed for specific protein complexes also applicable to higher-order assemblies observed in the cell? How is information from many cellular components decoded in order to fine-tune biological activity? It is increasingly recognised that protein interactions sample a wide-range of binding modes from ordered interactions with well-defined contact patterns to disordered interactions with heterogeneous contact patterns. In addition, protein interactions can change according to the cellular context, and certain protein regions may sample a multiplicity of binding modes (MBM). Thus, the binding modes of these context-dependent regions is controlled by the cellular milieu, enabling transitions between different cellular states. I will describe the cellular interaction landscape framework, to quantify the likelihood that proteins sample different binding modes in the cell. I will illustrate the applications of these concepts to describe changes between different higher-order assembly states in the cell, including conversion of dynamic clusters to amyloids, formation of virus-like capsid in regulation of synaptic plasticity and functional aggregates in muscle lineage development. Finally, I will present a novel type of cellular higher-order assembly, which is capable of rewiring protein networks in disease.
References
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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.
M. Vendruscolo*, M Fuxreiter* (2026) FuzDrop: Sequence-Based Prediction of the Propensity of Proteins for Liquid-Liquid Phase Separation and Aggregation. Nature Protocols 10.1038/s41596-025-01267-0
