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A multi-step nucleation process determines the kinetics of prion-like domain phase separation

Author

Listed:
  • Erik W. Martin

    (St. Jude Children’s Research Hospital)

  • Tyler S. Harmon

    (The Max Planck Institute for the Physics of Complex Systems)

  • Jesse B. Hopkins

    (Illinois Institute of Technology)

  • Srinivas Chakravarthy

    (Illinois Institute of Technology)

  • J. Jeremías Incicco

    (Washington University in St. Louis
    Washington University in St. Louis)

  • Peter Schuck

    (National Institutes of Health)

  • Andrea Soranno

    (Washington University in St. Louis
    Washington University in St. Louis)

  • Tanja Mittag

    (St. Jude Children’s Research Hospital)

Abstract

Compartmentalization by liquid-liquid phase separation (LLPS) has emerged as a ubiquitous mechanism underlying the organization of biomolecules in space and time. Here, we combine rapid-mixing time-resolved small-angle X-ray scattering (SAXS) approaches to characterize the assembly kinetics of a prototypical prion-like domain with equilibrium techniques that characterize its phase boundaries and the size distribution of clusters prior to phase separation. We find two kinetic regimes on the micro- to millisecond timescale that are distinguished by the size distribution of clusters. At the nanoscale, small complexes are formed with low affinity. After initial unfavorable complex assembly, additional monomers are added with higher affinity. At the mesoscale, assembly resembles classical homogeneous nucleation. Careful multi-pronged characterization is required for the understanding of condensate assembly mechanisms and will promote understanding of how the kinetics of biological phase separation is encoded in biomolecules.

Suggested Citation

  • Erik W. Martin & Tyler S. Harmon & Jesse B. Hopkins & Srinivas Chakravarthy & J. Jeremías Incicco & Peter Schuck & Andrea Soranno & Tanja Mittag, 2021. "A multi-step nucleation process determines the kinetics of prion-like domain phase separation," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24727-z
    DOI: 10.1038/s41467-021-24727-z
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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. Jaekyun Jeon & Wai-Ming Yau & Robert Tycko, 2023. "Early events in amyloid-β self-assembly probed by time-resolved solid state NMR and light scattering," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    3. 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.

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