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Phase separation-deficient TDP43 remains functional in splicing

Author

Listed:
  • Hermann Broder Schmidt

    (Stanford School of Medicine)

  • Ariana Barreau

    (Stanford School of Medicine)

  • Rajat Rohatgi

    (Stanford School of Medicine
    Stanford School of Medicine)

Abstract

Intrinsically disordered regions (IDRs) are often fast-evolving protein domains of low sequence complexity that can drive phase transitions and are commonly found in many proteins associated with neurodegenerative diseases, including the RNA processing factor TDP43. Yet, how phase separation contributes to the physiological functions of TDP43 in cells remains enigmatic. Here, we combine systematic mutagenesis guided by evolutionary sequence analysis with a live-cell reporter assay of TDP43 phase dynamics to identify regularly-spaced hydrophobic motifs separated by flexible, hydrophilic segments in the IDR as a key determinant of TDP43 phase properties. This heuristic framework allows customization of the material properties of TDP43 condensates to determine effects on splicing function. Remarkably, even a mutant that fails to phase-separate at physiological concentrations can still efficiently mediate the splicing of a quantitative, single-cell splicing reporter and endogenous targets. This suggests that the ability of TDP43 to phase-separate is not essential for its splicing function.

Suggested Citation

  • Hermann Broder Schmidt & Ariana Barreau & Rajat Rohatgi, 2019. "Phase separation-deficient TDP43 remains functional in splicing," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12740-2
    DOI: 10.1038/s41467-019-12740-2
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    Cited by:

    1. 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.
    2. Sheung Chun Ng & Abin Biswas & Trevor Huyton & Jürgen Schünemann & Simone Reber & Dirk Görlich, 2023. "Barrier properties of Nup98 FG phases ruled by FG motif identity and inter-FG spacer length," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    3. Miyuki Hayashi & Amandeep Girdhar & Ying-Hui Ko & Kevin M. Kim & Jacquelyn A. DePierro & Joseph R. Buchler & Nikhita Arunprakash & Aditya Bajaj & Gino Cingolani & Lin Guo, 2024. "Engineered NLS-chimera downregulates expression of aggregation-prone endogenous FUS," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

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