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Self-interaction of NPM1 modulates multiple mechanisms of liquid–liquid phase separation

Author

Listed:
  • Diana M. Mitrea

    (St. Jude Children’s Research Hospital)

  • Jaclyn A. Cika

    (St. Jude Children’s Research Hospital
    University of Tennessee Health Sciences Center
    NYU Langone Medical Center)

  • Christopher B. Stanley

    (Biology and Biomedical Sciences Group, Biology and Soft Matter Division, Oak Ridge National Laboratory)

  • Amanda Nourse

    (St. Jude Children’s Research Hospital
    Molecular Interaction Analysis Shared Resource, St. Jude Children’s Research Hospital)

  • Paulo L. Onuchic

    (The Scripps Research Institute)

  • Priya R. Banerjee

    (The Scripps Research Institute
    University of Buffalo)

  • Aaron H. Phillips

    (St. Jude Children’s Research Hospital)

  • Cheon-Gil Park

    (St. Jude Children’s Research Hospital)

  • Ashok A. Deniz

    (The Scripps Research Institute)

  • Richard W. Kriwacki

    (St. Jude Children’s Research Hospital
    University of Tennessee Health Sciences Center)

Abstract

Nucleophosmin (NPM1) is an abundant, oligomeric protein in the granular component of the nucleolus with roles in ribosome biogenesis. Pentameric NPM1 undergoes liquid–liquid phase separation (LLPS) via heterotypic interactions with nucleolar components, including ribosomal RNA (rRNA) and proteins which display multivalent arginine-rich linear motifs (R-motifs), and is integral to the liquid-like nucleolar matrix. Here we show that NPM1 can also undergo LLPS via homotypic interactions between its polyampholytic intrinsically disordered regions, a mechanism that opposes LLPS via heterotypic interactions. Using a combination of biophysical techniques, including confocal microscopy, SAXS, analytical ultracentrifugation, and single-molecule fluorescence, we describe how conformational changes within NPM1 control valency and switching between the different LLPS mechanisms. We propose that this newly discovered interplay between multiple LLPS mechanisms may influence the direction of vectorial pre-ribosomal particle assembly within, and exit from the nucleolus as part of the ribosome biogenesis process.

Suggested Citation

  • Diana M. Mitrea & Jaclyn A. Cika & Christopher B. Stanley & Amanda Nourse & Paulo L. Onuchic & Priya R. Banerjee & Aaron H. Phillips & Cheon-Gil Park & Ashok A. Deniz & Richard W. Kriwacki, 2018. "Self-interaction of NPM1 modulates multiple mechanisms of liquid–liquid phase separation," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03255-3
    DOI: 10.1038/s41467-018-03255-3
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    Cited by:

    1. Guocheng Fang & Zhen Qiao & Luqi Huang & Hui Zhu & Jun Xie & Tian Zhou & Zhongshu Xiong & I-Hsin Su & Dayong Jin & Yu-Cheng Chen, 2024. "Single-cell laser emitting cytometry for label-free nucleolus fingerprinting," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    2. Richoo B. Davis & Anushka Supakar & Aishwarya Kanchi Ranganath & Mahdi Muhammad Moosa & Priya R. Banerjee, 2024. "Heterotypic interactions can drive selective co-condensation of prion-like low-complexity domains of FET proteins and mammalian SWI/SNF complex," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    3. Furqan Dar & Samuel R. Cohen & Diana M. Mitrea & Aaron H. Phillips & Gergely Nagy & Wellington C. Leite & Christopher B. Stanley & Jeong-Mo Choi & Richard W. Kriwacki & Rohit V. Pappu, 2024. "Biomolecular condensates form spatially inhomogeneous network fluids," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    4. Kadi L. Saar & Rob M. Scrutton & Kotryna Bloznelyte & Alexey S. Morgunov & Lydia L. Good & Alpha A. Lee & Sarah A. Teichmann & Tuomas P. J. Knowles, 2024. "Protein Condensate Atlas from predictive models of heteromolecular condensate composition," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    5. Xiaocen Jin & Hikari Tanaka & Meihua Jin & Kyota Fujita & Hidenori Homma & Maiko Inotsume & Huang Yong & Kenichi Umeda & Noriyuki Kodera & Toshio Ando & Hitoshi Okazawa, 2023. "PQBP5/NOL10 maintains and anchors the nucleolus under physiological and osmotic stress conditions," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    6. Marta Vicioso-Mantis & Raquel Fueyo & Claudia Navarro & Sara Cruz-Molina & Wilfred F. J. Ijcken & Elena Rebollo & Álvaro Rada-Iglesias & Marian A. Martínez-Balbás, 2022. "JMJD3 intrinsically disordered region links the 3D-genome structure to TGFβ-dependent transcription activation," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    7. Edward Courchaine & Sara Gelles-Watnick & Martin Machyna & Korinna Straube & Sarah Sauyet & Jade Enright & Karla M. Neugebauer, 2022. "The coilin N-terminus mediates multivalent interactions between coilin and Nopp140 to form and maintain Cajal bodies," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    8. Yongli Shan & Yanqi Zhang & Yanxing Wei & Cong Zhang & Huaisong Lin & Jiangping He & Junwei Wang & Wenjing Guo & Heying Li & Qianyu Chen & Tiancheng Zhou & Qi Xing & Yancai Liu & Jiekai Chen & Guangji, 2024. "METTL3/METTL14 maintain human nucleoli integrity by mediating SUV39H1/H2 degradation," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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