Electrostatics of salt-dependent reentrant phase behaviors highlights diverse roles of ATP in biomolecular condensates

Liquid-liquid phase separation (LLPS) involving intrinsically disordered protein regions (IDRs) is a major physical mechanism for biological membraneless compartmentalization. The multifaceted electrostatic effects in these biomolecular condensates are exemplified here by experimental and theoretica...

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Main Authors: Yi-Hsuan Lin, Tae Hun Kim, Suman Das, Tanmoy Pal, Jonas Wessén, Atul Kaushik Rangadurai, Lewis E Kay, Julie D Forman-Kay, Hue Sun Chan
Format: Article
Language:English
Published: eLife Sciences Publications Ltd 2025-03-01
Series:eLife
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Online Access:https://elifesciences.org/articles/100284
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Summary:Liquid-liquid phase separation (LLPS) involving intrinsically disordered protein regions (IDRs) is a major physical mechanism for biological membraneless compartmentalization. The multifaceted electrostatic effects in these biomolecular condensates are exemplified here by experimental and theoretical investigations of the different salt- and ATP-dependent LLPSs of an IDR of messenger RNA-regulating protein Caprin1 and its phosphorylated variant pY-Caprin1, exhibiting, for example, reentrant behaviors in some instances but not others. Experimental data are rationalized by physical modeling using analytical theory, molecular dynamics, and polymer field-theoretic simulations, indicating that interchain ion bridges enhance LLPS of polyelectrolytes such as Caprin1 and the high valency of ATP-magnesium is a significant factor for its colocalization with the condensed phases, as similar trends are observed for other IDRs. The electrostatic nature of these features complements ATP’s involvement in π-related interactions and as an amphiphilic hydrotrope, underscoring a general role of biomolecular condensates in modulating ion concentrations and its functional ramifications.
ISSN:2050-084X