Programmable de novo designed coiled coil-mediated phase separation in mammalian cells

Maruša Ramšak, Dominique A. Ramirez, Loren E. Hough, Michael R. Shirts, Sara Vidmar, Kristina Eleršič Filipič, Gregor Anderluh and Roman Jerala ()
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Maruša Ramšak: National Institute of Chemistry
Dominique A. Ramirez: University of Colorado Boulder
Loren E. Hough: University of Colorado Boulder
Michael R. Shirts: University of Colorado Boulder
Sara Vidmar: National Institute of Chemistry
Kristina Eleršič Filipič: National Institute of Chemistry
Gregor Anderluh: National Institute of Chemistry
Roman Jerala: National Institute of Chemistry

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract Membraneless liquid compartments based on phase-separating biopolymers have been observed in diverse cell types and attributed to weak multivalent interactions predominantly based on intrinsically disordered domains. The design of liquid-liquid phase separated (LLPS) condensates based on de novo designed tunable modules that interact in a well-understood, controllable manner could improve our understanding of this phenomenon and enable the introduction of new features. Here we report the construction of CC-LLPS in mammalian cells, based on designed coiled-coil (CC) dimer-forming modules, where the stability of CC pairs, their number, linkers, and sequential arrangement govern the transition between diffuse, liquid and immobile condensates and are corroborated by coarse-grained molecular simulations. Through modular design, we achieve multiple coexisting condensates, chemical regulation of LLPS, condensate fusion, formation from either one or two polypeptide components or LLPS regulation by a third polypeptide chain. These findings provide further insights into the principles underlying LLPS formation and a design platform for controlling biological processes.

Date: 2023
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DOI: 10.1038/s41467-023-43742-w

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