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Molecular and environmental determinants of biomolecular condensate formation

Abstract

Biomolecular condensate formation has been implicated in a host of biological processes and has found relevance in biology and disease. Understanding the physical principles and underlying characteristics of how these macromolecular assemblies form and are regulated has become a central focus of the field. In this Review, we introduce features of phase-separating biomolecules from a general physical viewpoint and highlight how molecular features, including affinity, valence and a competition between inter- and intramolecular contacts, affect phase separation. We then discuss sequence properties of proteins that serve to mediate intermolecular interactions. Finally, we review how the intracellular environment can affect structural and sequence determinants of proteins and modulate physical parameters of their phase transitions. The works reviewed highlight that a complex interplay exists between structure, sequence and environmental determinants in the formation of biomolecular condensates.

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Fig. 1: Condensate formation can involve and influence all levels of macromolecular organization.
Fig. 2: Theoretical frameworks of polymer phase separation establish a connection between physical parameters of monomers and condensate formation propensity.
Fig. 3: Interaction specificity in biomolecular condensates.
Fig. 4: Cellular adaptation and the environment can influence phase separation.

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Acknowledgements

This work was supported by the European Research Council under the European Union’s Horizon 2020 research and innovation program (grant agreement number 819318), by the Israel Science Foundation (grant number 1452/18), by a research grant from A.-M. Boucher and by research grants from the Estelle Funk Foundation, the Estate of Fannie Sherr, the Estate of Albert Delighter, the Merle S. Cahn Foundation, Mrs. Mildred S. Gosden, the Estate of Elizabeth Wachsman and the Arnold Bortman Family Foundation.

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Villegas, J.A., Heidenreich, M. & Levy, E.D. Molecular and environmental determinants of biomolecular condensate formation. Nat Chem Biol 18, 1319–1329 (2022). https://doi.org/10.1038/s41589-022-01175-4

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