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Programmable de novo designed coiled coil-mediated phase separation in mammalian cells
ID Ramšak, Maruša (Author), ID Ramirez, Dominique A. (Author), ID Hough, Loren E. (Author), ID Shirts, Michael R. (Author), ID Vidmar, Sara (Author), ID Eleršič Filipič, Kristina (Author), ID Anderluh, Gregor (Author), ID Jerala, Roman (Author)

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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.

Language:English
Keywords:protein aggregation, protein design, synthetic biology
Work type:Article
Typology:1.01 - Original Scientific Article
Organization:MF - Faculty of Medicine
Publication status:Published
Publication version:Version of Record
Year:2023
Number of pages:15 str.
Numbering:Vol. 14, art. 7973
PID:20.500.12556/RUL-164452 This link opens in a new window
UDC:577
ISSN on article:2041-1723
DOI:10.1038/s41467-023-43742-w This link opens in a new window
COBISS.SI-ID:177039875 This link opens in a new window
Publication date in RUL:25.10.2024
Views:120
Downloads:129
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Record is a part of a journal

Title:Nature communications
Shortened title:Nat. commun.
Publisher:Springer Nature
ISSN:2041-1723
COBISS.SI-ID:2315876 This link opens in a new window

Licences

License:CC BY 4.0, Creative Commons Attribution 4.0 International
Link:http://creativecommons.org/licenses/by/4.0/
Description:This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

Language:Slovenian
Keywords:biokemija, biopolimeri, biološki procesi, celice, sesalci, simulacije

Projects

Funder:ARRS - Slovenian Research Agency
Project number:P4-0176
Name:Sintezna biologija in imunologija

Funder:ARRS - Slovenian Research Agency
Project number:P3-0289
Name:Značilnosti malignih neoplazem, pomembnih za diagnozo ter napoved poteka bolezni in izida zdravljenja

Funder:ARRS - Slovenian Research Agency
Project number:J7-4640
Name:Inovativna imunoterapija raka preko CAR T celic (CARRS)

Funder:ARRS - Slovenian Research Agency
Project number:J1-4406
Name:CC-Trigger: izpodrivanje proteinskih obvitih vijačnic s pomočjo oprimkov omogoča kinetični nadzor proteinskih sestavov in napredne naprave z več stanji

Funder:EC - European Commission
Funding programme:H2020
Project number:787115
Name:Molecular machines based on coiled-coil protein origami
Acronym:MaCChines

Funder:NIH - National Institutes of Health
Funding programme:Molecular Biophysics Training Program
Project number:T32GM065103

Funder:NSF - National Science Foundation
Funding programme:Directorate for Biological Sciences
Project number:1943488
Name:CAREER: Molecular mechanisms underlying yeast cellular starvation tolerance; spatial reasoning to increase STEM participation

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