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Nucleation landscape of biomolecular condensates

Author

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  • Shunsuke F. Shimobayashi

    (Princeton University)

  • Pierre Ronceray

    (Princeton University
    Université de Toulon, CNRS, CPT, Turing Center for Living Systems)

  • David W. Sanders

    (Princeton University)

  • Mikko P. Haataja

    (Princeton University
    Princeton University)

  • Clifford P. Brangwynne

    (Princeton University
    Princeton University
    Princeton University)

Abstract

All structures within living cells must form at the right time and place. This includes condensates such as the nucleolus, Cajal bodies and stress granules, which form via liquid–liquid phase separation of biomolecules, particularly proteins enriched in intrinsically disordered regions (IDRs)1,2. In non-living systems, the initial stages of nucleated phase separation arise when thermal fluctuations overcome an energy barrier due to surface tension. This phenomenon can be modelled by classical nucleation theory (CNT), which describes how the rate of droplet nucleation depends on the degree of supersaturation, whereas the location at which droplets appear is controlled by interfacial heterogeneities3,4. However, it remains unknown whether this framework applies in living cells, owing to the multicomponent and highly complex nature of the intracellular environment, including the presence of diverse IDRs, whose specificity of biomolecular interactions is unclear5–8. Here we show that despite this complexity, nucleation in living cells occurs through a physical process similar to that in inanimate materials, but the efficacy of nucleation sites can be tuned by their biomolecular features. By quantitatively characterizing the nucleation kinetics of endogenous and biomimetic condensates in living cells, we find that key features of condensate nucleation can be quantitatively understood through a CNT-like theoretical framework. Nucleation rates can be substantially enhanced by compatible biomolecular (IDR) seeds, and the kinetics of cellular processes can impact condensate nucleation rates and specificity of location. This quantitative framework sheds light on the intracellular nucleation landscape, and paves the way for engineering synthetic condensates precisely positioned in space and time.

Suggested Citation

  • Shunsuke F. Shimobayashi & Pierre Ronceray & David W. Sanders & Mikko P. Haataja & Clifford P. Brangwynne, 2021. "Nucleation landscape of biomolecular condensates," Nature, Nature, vol. 599(7885), pages 503-506, November.
  • Handle: RePEc:nat:nature:v:599:y:2021:i:7885:d:10.1038_s41586-021-03905-5
    DOI: 10.1038/s41586-021-03905-5
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    Citations

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    Cited by:

    1. Juan Manuel Valverde & Geronimo Dubra & Michael Phillips & Austin Haider & Carlos Elena-Real & Aurélie Fournet & Emile Alghoul & Dhanvantri Chahar & Nuria Andrés-Sanchez & Matteo Paloni & Pau Bernadó , 2023. "A cyclin-dependent kinase-mediated phosphorylation switch of disordered protein condensation," Nature Communications, Nature, vol. 14(1), pages 1-23, December.
    2. Darren B. McAffee & Mark K. O’Dair & Jenny J. Lin & Shalini T. Low-Nam & Kiera B. Wilhelm & Sungi Kim & Shumpei Morita & Jay T. Groves, 2022. "Discrete LAT condensates encode antigen information from single pMHC:TCR binding events," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    3. Chenyang Lan & Juhyeong Kim & Svenja Ulferts & Fernando Aprile-Garcia & Sophie Weyrauch & Abhinaya Anandamurugan & Robert Grosse & Ritwick Sawarkar & Aleks Reinhardt & Thorsten Hugel, 2023. "Quantitative real-time in-cell imaging reveals heterogeneous clusters of proteins prior to condensation," Nature Communications, Nature, vol. 14(1), pages 1-8, December.
    4. Jingru Fang & Guillaume Castillon & Sebastien Phan & Sara McArdle & Chitra Hariharan & Aiyana Adams & Mark H. Ellisman & Ashok A. Deniz & Erica Ollmann Saphire, 2023. "Spatial and functional arrangement of Ebola virus polymerase inside phase-separated viral factories," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    5. Juan Du & Keunhwa Kim & Meng Chen, 2024. "Distinguishing individual photobodies using Oligopaints reveals thermo-sensitive and -insensitive phytochrome B condensation at distinct subnuclear locations," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    6. Jing Tao & Yanping Zeng & Bin Dai & Yin Liu & Xiaohan Pan & Li-Qiang Wang & Jie Chen & Yu Zhou & Zuneng Lu & Liwei Xie & Yi Liang, 2023. "Excess PrPC inhibits muscle cell differentiation via miRNA-enhanced liquid–liquid phase separation implicated in myopathy," Nature Communications, Nature, vol. 14(1), pages 1-22, December.

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