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The Regulatory Roles of Intrinsically Disordered Linker in VRN1-DNA Phase Separation

Biomacromolecules often form condensates to function in cells. VRN1 is a transcriptional repressor that plays a key role in plant vernalization. Containing two DNA-binding domains connected by an intrinsically disordered linker (IDL), VRN1 was shown to undergo liquid-like phase separation with DNA,...

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Autores principales: Huang, Qiaojing, Wang, Yanyan, Liu, Zhirong, Lai, Luhua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9106000/
https://www.ncbi.nlm.nih.gov/pubmed/35562982
http://dx.doi.org/10.3390/ijms23094594
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author Huang, Qiaojing
Wang, Yanyan
Liu, Zhirong
Lai, Luhua
author_facet Huang, Qiaojing
Wang, Yanyan
Liu, Zhirong
Lai, Luhua
author_sort Huang, Qiaojing
collection PubMed
description Biomacromolecules often form condensates to function in cells. VRN1 is a transcriptional repressor that plays a key role in plant vernalization. Containing two DNA-binding domains connected by an intrinsically disordered linker (IDL), VRN1 was shown to undergo liquid-like phase separation with DNA, and the length and charge pattern of IDL play major regulatory roles. However, the underlying mechanism remains elusive. Using a polymer chain model and lattice-based Monte-Carlo simulations, we comprehensively investigated how the IDL regulates VRN1 and DNA phase separation. Using a worm-like chain model, we showed that the IDL controls the binding affinity of VRN1 to DNA, by modulating the effective local concentration of the VRN1 DNA-binding domains. The predicted binding affinities, under different IDL lengths, were in good agreement with previously reported experimental results. Our simulation of the phase diagrams of the VRN1 variants with neutral IDLs and DNA revealed that the ability of phase separation first increased and then decreased, along with the increase in the linker length. The strongest phase separation ability was achieved when the linker length was between 40 and 80 residues long. Adding charged patches to the IDL resulted in robust phase separation that changed little with IDL length variations. Our study provides mechanism insights on how IDL regulates VRN1 and DNA phase separation, and why naturally occurring VRN1-like proteins evolve to contain the charge segregated IDL sequences, which may also shed light on the molecular mechanisms of other IDL-regulated phase separation processes in living cells.
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spelling pubmed-91060002022-05-14 The Regulatory Roles of Intrinsically Disordered Linker in VRN1-DNA Phase Separation Huang, Qiaojing Wang, Yanyan Liu, Zhirong Lai, Luhua Int J Mol Sci Article Biomacromolecules often form condensates to function in cells. VRN1 is a transcriptional repressor that plays a key role in plant vernalization. Containing two DNA-binding domains connected by an intrinsically disordered linker (IDL), VRN1 was shown to undergo liquid-like phase separation with DNA, and the length and charge pattern of IDL play major regulatory roles. However, the underlying mechanism remains elusive. Using a polymer chain model and lattice-based Monte-Carlo simulations, we comprehensively investigated how the IDL regulates VRN1 and DNA phase separation. Using a worm-like chain model, we showed that the IDL controls the binding affinity of VRN1 to DNA, by modulating the effective local concentration of the VRN1 DNA-binding domains. The predicted binding affinities, under different IDL lengths, were in good agreement with previously reported experimental results. Our simulation of the phase diagrams of the VRN1 variants with neutral IDLs and DNA revealed that the ability of phase separation first increased and then decreased, along with the increase in the linker length. The strongest phase separation ability was achieved when the linker length was between 40 and 80 residues long. Adding charged patches to the IDL resulted in robust phase separation that changed little with IDL length variations. Our study provides mechanism insights on how IDL regulates VRN1 and DNA phase separation, and why naturally occurring VRN1-like proteins evolve to contain the charge segregated IDL sequences, which may also shed light on the molecular mechanisms of other IDL-regulated phase separation processes in living cells. MDPI 2022-04-21 /pmc/articles/PMC9106000/ /pubmed/35562982 http://dx.doi.org/10.3390/ijms23094594 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Huang, Qiaojing
Wang, Yanyan
Liu, Zhirong
Lai, Luhua
The Regulatory Roles of Intrinsically Disordered Linker in VRN1-DNA Phase Separation
title The Regulatory Roles of Intrinsically Disordered Linker in VRN1-DNA Phase Separation
title_full The Regulatory Roles of Intrinsically Disordered Linker in VRN1-DNA Phase Separation
title_fullStr The Regulatory Roles of Intrinsically Disordered Linker in VRN1-DNA Phase Separation
title_full_unstemmed The Regulatory Roles of Intrinsically Disordered Linker in VRN1-DNA Phase Separation
title_short The Regulatory Roles of Intrinsically Disordered Linker in VRN1-DNA Phase Separation
title_sort regulatory roles of intrinsically disordered linker in vrn1-dna phase separation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9106000/
https://www.ncbi.nlm.nih.gov/pubmed/35562982
http://dx.doi.org/10.3390/ijms23094594
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