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Small molecules as potent biphasic modulators of protein liquid-liquid phase separation

Author

Listed:
  • W. Michael Babinchak

    (Case Western Reserve University)

  • Benjamin K. Dumm

    (Case Western Reserve University)

  • Sarah Venus

    (Case Western Reserve University)

  • Solomiia Boyko

    (Case Western Reserve University)

  • Andrea A. Putnam

    (Case Western Reserve University
    Johns Hopkins School of Medicine)

  • Eckhard Jankowsky

    (Case Western Reserve University)

  • Witold K. Surewicz

    (Case Western Reserve University)

Abstract

Liquid-liquid phase separation (LLPS) of proteins that leads to formation of membrane-less organelles is critical to many biochemical processes in the cell. However, dysregulated LLPS can also facilitate aberrant phase transitions and lead to protein aggregation and disease. Accordingly, there is great interest in identifying small molecules that modulate LLPS. Here, we demonstrate that 4,4’-dianilino-1,1’-binaphthyl-5,5’-disulfonic acid (bis-ANS) and similar compounds are potent biphasic modulators of protein LLPS. Depending on context, bis-ANS can both induce LLPS de novo as well as prevent formation of homotypic liquid droplets. Our study also reveals the mechanisms by which bis-ANS and related compounds modulate LLPS and identify key chemical features of small molecules required for this activity. These findings may provide a foundation for the rational design of small molecule modulators of LLPS with therapeutic value.

Suggested Citation

  • W. Michael Babinchak & Benjamin K. Dumm & Sarah Venus & Solomiia Boyko & Andrea A. Putnam & Eckhard Jankowsky & Witold K. Surewicz, 2020. "Small molecules as potent biphasic modulators of protein liquid-liquid phase separation," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-19211-z
    DOI: 10.1038/s41467-020-19211-z
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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. 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.
    3. Jun Sun & Jiale Qu & Cai Zhao & Xinyao Zhang & Xinyu Liu & Jia Wang & Chao Wei & Xinyi Liu & Mulan Wang & Pengguihang Zeng & Xiuxiao Tang & Xiaoru Ling & Li Qing & Shaoshuai Jiang & Jiahao Chen & Tara, 2024. "Precise prediction of phase-separation key residues by machine learning," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    4. 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.
    5. Hao-Yu Chuang & Ruei-Yu He & Yung-An Huang & Wan-Ting Hsu & Ya-Jen Cheng & Zheng-Rong Guo & Niaz Wali & Ing-Shouh Hwang & Jiun-Jie Shie & Joseph Jen-Tse Huang, 2024. "Engineered droplet-forming peptide as photocontrollable phase modulator for fused in sarcoma protein," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    6. Xi Li & Linwei Yu & Xikai Liu & Tianyi Shi & Yu Zhang & Yushuo Xiao & Chen Wang & Liangliang Song & Ning Li & Xinran Liu & Yuchen Chen & Robert B. Petersen & Xiang Cheng & Weikang Xue & Yanxun V. Yu &, 2024. "β-synuclein regulates the phase transitions and amyloid conversion of α-synuclein," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    7. 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.

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