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Linking modulation of bio-molecular phase behaviour with collective interactions
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Linking modulation of bio-molecular phase behaviour with collective interactions
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Paper
Linking modulation of bio-molecular phase behaviour with collective interactions
2023,2024
Overview
Bio-molecular condensates formed in the cytoplasm of cells are increasingly recognised as key spatiotemporal organisers of living matter and are implicated in a wide range of functional or pathological processes. This opens up a new avenue for condensate-based applications and a crucial step in controlling this process is to understand the underlying interactions driving their formation or dissolution. However, these condensates are highly multi-component assemblies and many inter-component interactions are present, rendering it difficult to identify key drivers of phase separation. In this work, we employ the recently formulated dominance analysis to modulations of condensate formation, centred around dilute phase solute concentration measurements. We posit that mechanisms of action of modulators can be categorised into 4 generic classes with respect to a target solute, motivated by theoretical insights. These classes serve as a general guide towards deducing possible mechanisms on the molecular level, which can be complemented by orthogonal measurements. As a case study, we investigate the modulation of suramin on condensates formed by G3BP1 and RNA, and the dominance measurements point towards a dissolution mechanism where suramin acts on G3BP1 to disrupt G3BP1/RNA interactions, as confirmed by a diffusional sizing assay. Our approach and the dominance framework have a high degree of adaptability and can be applied in many other condensate-forming systems.Competing Interest StatementParts of this work have been the subject of a patent application filed by Cambridge Enterprise Limited, a fully owned subsidiary of the University of Cambridge. T. P. J. K. and P. St G. H. are founders, and W. E. A., T. K., N. E. and S. Q. are employees of Transition Bio Ltd.Footnotes* typo correction
Publisher
Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
Subject
