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A modular platform for engineering function of natural and synthetic biomolecular condensates

View ORCID ProfileKeren Lasker, View ORCID ProfileSteven Boeynaems, View ORCID ProfileVinson Lam, View ORCID ProfileEmma Stainton, View ORCID ProfileMaarten Jacquemyn, View ORCID ProfileDirk Daelemans, View ORCID ProfileElizabeth Villa, View ORCID ProfileAlex S. Holehouse, View ORCID ProfileAaron D. Gitler, View ORCID ProfileLucy Shapiro
doi: https://doi.org/10.1101/2021.02.03.429226
Keren Lasker
1Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
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Steven Boeynaems
2Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA
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Vinson Lam
3Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA
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Emma Stainton
1Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
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Maarten Jacquemyn
4KU Leuven Department of Microbiology, Immunology, and Transplantation, Laboratory of Virology and Chemotherapy, Rega Institute, KU Leuven, 3000 Leuven, Belgium
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Dirk Daelemans
4KU Leuven Department of Microbiology, Immunology, and Transplantation, Laboratory of Virology and Chemotherapy, Rega Institute, KU Leuven, 3000 Leuven, Belgium
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Elizabeth Villa
3Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA
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  • ORCID record for Elizabeth Villa
Alex S. Holehouse
5Department of Biochemistry and Molecular Biophysics, Washington University in St. Louis, St. Louis, MO 63110, USA
6Center for Science and Engineering of Living Systems (CSELS), Washington University in St. Louis, St. Louis, MO 63130, USA
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Aaron D. Gitler
2Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA
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Lucy Shapiro
1Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
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  • For correspondence: shapiro@stanford.edu
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Abstract

Phase separation is emerging as a universal principle for how cells use dynamic subcompartmentalization to organize biochemical reactions in time and space1,2. Yet, whether the emergent physical properties of these biomolecular condensates are important for their biological function remains unclear. The intrinsically disordered protein PopZ forms membraneless condensates at the poles of the bacterium Caulobacter crescentus and selectively sequesters kinase-signaling cascades to regulate asymmetric cell division3–5. By dissecting the molecular grammar underlying PopZ phase separation, we find that unlike many eukaryotic examples, where unstructured regions drive condensation6,7, a structured domain of PopZ drives condensation, while conserved repulsive features of the disordered region modulate material properties. By generating rationally designed PopZ mutants, we find that the exact material properties of PopZ condensates directly determine cellular fitness, providing direct evidence for the physiological importance of the emergent properties of biomolecular condensates. Our work codifies a clear set of design principles illuminating how sequence variation in a disordered domain alters the function of a widely conserved bacterial condensate. We used these insights to repurpose PopZ as a modular platform for generating synthetic condensates of tunable function in human cells.

Competing Interest Statement

A.S.H. is a scientific consultant with Dewpoint Therapeutics. A.D.G. has served as a consultant for Aquinnah Pharmaceuticals, Prevail Therapeutics and Third Rock Ventures and is a scientific founder of Maze Therapeutics. L.S. is on the board of Pacific Biosciences. K.L., S.B, A.D.G, and L.S. have submitted a patent application relating to pieces of this work (PCT/US2020/063245).

Footnotes

  • ↵# emails: agitler{at}stanford.edu, shapiro{at}stanford.edu

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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A modular platform for engineering function of natural and synthetic biomolecular condensates
Keren Lasker, Steven Boeynaems, Vinson Lam, Emma Stainton, Maarten Jacquemyn, Dirk Daelemans, Elizabeth Villa, Alex S. Holehouse, Aaron D. Gitler, Lucy Shapiro
bioRxiv 2021.02.03.429226; doi: https://doi.org/10.1101/2021.02.03.429226
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A modular platform for engineering function of natural and synthetic biomolecular condensates
Keren Lasker, Steven Boeynaems, Vinson Lam, Emma Stainton, Maarten Jacquemyn, Dirk Daelemans, Elizabeth Villa, Alex S. Holehouse, Aaron D. Gitler, Lucy Shapiro
bioRxiv 2021.02.03.429226; doi: https://doi.org/10.1101/2021.02.03.429226

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