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Reentrant liquid condensate phase of proteins is stabilized by hydrophobic and non-ionic interactions

Author

Listed:
  • Georg Krainer

    (University of Cambridge)

  • Timothy J. Welsh

    (University of Cambridge)

  • Jerelle A. Joseph

    (University of Cambridge, J J Thomson Avenue
    University of Cambridge
    University of Cambridge, Lensfield Road)

  • Jorge R. Espinosa

    (University of Cambridge, J J Thomson Avenue
    University of Cambridge
    University of Cambridge, Lensfield Road)

  • Sina Wittmann

    (Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG)
    Technische Universität Dresden, Tatzberg 47/49)

  • Ella Csilléry

    (University of Cambridge)

  • Akshay Sridhar

    (University of Cambridge, J J Thomson Avenue
    University of Cambridge
    University of Cambridge, Lensfield Road)

  • Zenon Toprakcioglu

    (University of Cambridge)

  • Giedre Gudiškytė

    (University of Cambridge)

  • Magdalena A. Czekalska

    (University of Cambridge
    Institute of Physical Chemistry, Polish Academy of Sciences, Kasprzaka)

  • William E. Arter

    (University of Cambridge)

  • Jordina Guillén-Boixet

    (Technische Universität Dresden, Tatzberg 47/49)

  • Titus M. Franzmann

    (Technische Universität Dresden, Tatzberg 47/49)

  • Seema Qamar

    (University of Cambridge)

  • Peter St George-Hyslop

    (University of Cambridge
    University of Toronto and University Health Network)

  • Anthony A. Hyman

    (Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG))

  • Rosana Collepardo-Guevara

    (University of Cambridge, J J Thomson Avenue
    University of Cambridge
    University of Cambridge, Lensfield Road)

  • Simon Alberti

    (Technische Universität Dresden, Tatzberg 47/49)

  • Tuomas P. J. Knowles

    (University of Cambridge
    University of Cambridge, J J Thomson Avenue)

Abstract

Liquid–liquid phase separation of proteins underpins the formation of membraneless compartments in living cells. Elucidating the molecular driving forces underlying protein phase transitions is therefore a key objective for understanding biological function and malfunction. Here we show that cellular proteins, which form condensates at low salt concentrations, including FUS, TDP-43, Brd4, Sox2, and Annexin A11, can reenter a phase-separated regime at high salt concentrations. By bringing together experiments and simulations, we demonstrate that this reentrant phase transition in the high-salt regime is driven by hydrophobic and non-ionic interactions, and is mechanistically distinct from the low-salt regime, where condensates are additionally stabilized by electrostatic forces. Our work thus sheds light on the cooperation of hydrophobic and non-ionic interactions as general driving forces in the condensation process, with important implications for aberrant function, druggability, and material properties of biomolecular condensates.

Suggested Citation

  • Georg Krainer & Timothy J. Welsh & Jerelle A. Joseph & Jorge R. Espinosa & Sina Wittmann & Ella Csilléry & Akshay Sridhar & Zenon Toprakcioglu & Giedre Gudiškytė & Magdalena A. Czekalska & William E. , 2021. "Reentrant liquid condensate phase of proteins is stabilized by hydrophobic and non-ionic interactions," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21181-9
    DOI: 10.1038/s41467-021-21181-9
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    Cited by:

    1. William E. Arter & Runzhang Qi & Nadia A. Erkamp & Georg Krainer & Kieran Didi & Timothy J. Welsh & Julia Acker & Jonathan Nixon-Abell & Seema Qamar & Jordina Guillén-Boixet & Titus M. Franzmann & Dav, 2022. "Biomolecular condensate phase diagrams with a combinatorial microdroplet platform," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    2. David Q. P. Reis & Sara Pereira & Ana P. Ramos & Pedro M. Pereira & Leonor Morgado & Joana Calvário & Adriano O. Henriques & Mónica Serrano & Ana S. Pina, 2024. "Catalytic peptide-based coacervates for enhanced function through structural organization and substrate specificity," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    3. Aishwarya Agarwal & Lisha Arora & Sandeep K. Rai & Anamika Avni & Samrat Mukhopadhyay, 2022. "Spatiotemporal modulations in heterotypic condensates of prion and α-synuclein control phase transitions and amyloid conversion," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    4. Saumyak Mukherjee & Lars V. Schäfer, 2023. "Thermodynamic forces from protein and water govern condensate formation of an intrinsically disordered protein domain," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    5. Yuri Hong & Saeed Najafi & Thomas Casey & Joan-Emma Shea & Song-I Han & Dong Soo Hwang, 2022. "Hydrophobicity of arginine leads to reentrant liquid-liquid phase separation behaviors of arginine-rich proteins," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    6. Georg Krainer & Kadi L. Saar & William E. Arter & Timothy J. Welsh & Magdalena A. Czekalska & Raphaël P. B. Jacquat & Quentin Peter & Walther C. Traberg & Arvind Pujari & Akhila K. Jayaram & Pavankuma, 2023. "Direct digital sensing of protein biomarkers in solution," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    7. Andres R. Tejedor & Ignacio Sanchez-Burgos & Maria Estevez-Espinosa & Adiran Garaizar & Rosana Collepardo-Guevara & Jorge Ramirez & Jorge R. Espinosa, 2022. "Protein structural transitions critically transform the network connectivity and viscoelasticity of RNA-binding protein condensates but RNA can prevent it," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    8. Manisha Poudyal & Komal Patel & Laxmikant Gadhe & Ajay Singh Sawner & Pradeep Kadu & Debalina Datta & Semanti Mukherjee & Soumik Ray & Ambuja Navalkar & Siddhartha Maiti & Debdeep Chatterjee & Jyoti D, 2023. "Intermolecular interactions underlie protein/peptide phase separation irrespective of sequence and structure at crowded milieu," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    9. Hong Zhang & Huazhang Guo & Danni Li & Yiling Zhang & Shengnan Zhang & Wenyan Kang & Cong Liu & Weidong Le & Liang Wang & Dan Li & Bin Dai, 2024. "Halogen doped graphene quantum dots modulate TDP-43 phase separation and aggregation in the nucleus," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    10. Tuan Nguyen & Sai Li & Jeremy T-H Chang & John W. Watters & Htet Ng & Adewola Osunsade & Yael David & Shixin Liu, 2022. "Chromatin sequesters pioneer transcription factor Sox2 from exerting force on DNA," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    11. Andrew Z. Lin & Kiersten M. Ruff & Furqan Dar & Ameya Jalihal & Matthew R. King & Jared M. Lalmansingh & Ammon E. Posey & Nadia A. Erkamp & Ian Seim & Amy S. Gladfelter & Rohit V. Pappu, 2023. "Dynamical control enables the formation of demixed biomolecular condensates," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    12. Tomas Sneideris & Nadia A. Erkamp & Hannes Ausserwöger & Kadi L. Saar & Timothy J. Welsh & Daoyuan Qian & Kai Katsuya-Gaviria & Margaret L. L. Y. Johncock & Georg Krainer & Alexander Borodavka & Tuoma, 2023. "Targeting nucleic acid phase transitions as a mechanism of action for antimicrobial peptides," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    13. Georg Krainer & Raphael P. B. Jacquat & Matthias M. Schneider & Timothy J. Welsh & Jieyuan Fan & Quentin A. E. Peter & Ewa A. Andrzejewska & Greta Šneiderienė & Magdalena A. Czekalska & Hannes Ausserw, 2024. "Single-molecule digital sizing of proteins in solution," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    14. Hema M. Swasthi & Joseph L. Basalla & Claire E. Dudley & Anthony G. Vecchiarelli & Matthew R. Chapman, 2023. "Cell surface-localized CsgF condensate is a gatekeeper in bacterial curli subunit secretion," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    15. Daniel C. Carrettiero & Maria C. Almeida & Andrew P. Longhini & Jennifer N. Rauch & Dasol Han & Xuemei Zhang & Saeed Najafi & Jason E. Gestwicki & Kenneth S. Kosik, 2022. "Stress routes clients to the proteasome via a BAG2 ubiquitin-independent degradation condensate," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    16. Ashish Joshi & Anuja Walimbe & Snehasis Sarkar & Lisha Arora & Gaganpreet Kaur & Prince Jhandai & Dhruba Chatterjee & Indranil Banerjee & Samrat Mukhopadhyay, 2024. "Intermolecular energy migration via homoFRET captures the modulation in the material property of phase-separated biomolecular condensates," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    17. Avigail Baruch Leshem & Sian Sloan-Dennison & Tlalit Massarano & Shavit Ben-David & Duncan Graham & Karen Faulds & Hugo E. Gottlieb & Jordan H. Chill & Ayala Lampel, 2023. "Biomolecular condensates formed by designer minimalistic peptides," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    18. Bikash Chandra Swain & Pascale Sarkis & Vanessa Ung & Sabrina Rousseau & Laurent Fernandez & Ani Meltonyan & V. Esperance Aho & Davide Mercadante & Cameron D. Mackereth & Mikayel Aznauryan, 2024. "Disordered regions of human eIF4B orchestrate a dynamic self-association landscape," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

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