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Cooperative stability renders protein complex formation more robust and controllable

Protein complexes are the fundamental units of many biological functions. Despite their many advantages, one major adverse impact of protein complexes is accumulations of unassembled subunits that may disrupt other processes or exert cytotoxic effects. Synthesis of excess subunits can be inhibited v...

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Autores principales: Hsu, Kuan-Lun, Yen, Hsueh-Chi S., Yeang, Chen-Hsiang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9213465/
https://www.ncbi.nlm.nih.gov/pubmed/35729235
http://dx.doi.org/10.1038/s41598-022-14362-z
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author Hsu, Kuan-Lun
Yen, Hsueh-Chi S.
Yeang, Chen-Hsiang
author_facet Hsu, Kuan-Lun
Yen, Hsueh-Chi S.
Yeang, Chen-Hsiang
author_sort Hsu, Kuan-Lun
collection PubMed
description Protein complexes are the fundamental units of many biological functions. Despite their many advantages, one major adverse impact of protein complexes is accumulations of unassembled subunits that may disrupt other processes or exert cytotoxic effects. Synthesis of excess subunits can be inhibited via negative feedback control or they can be degraded more efficiently than assembled subunits, with this latter being termed cooperative stability. Whereas controlled synthesis of complex subunits has been investigated extensively, how cooperative stability acts in complex formation remains largely unexplored. To fill this knowledge gap, we have built quantitative models of heteromeric complexes with or without cooperative stability and compared their behaviours in the presence of synthesis rate variations. A system displaying cooperative stability is robust against synthesis rate variations as it retains high dimer/monomer ratios across a broad range of parameter configurations. Moreover, cooperative stability can alleviate the constraint of limited supply of a given subunit and makes complex abundance more responsive to unilateral upregulation of another subunit. We also conducted an in silico experiment to comprehensively characterize and compare four types of circuits that incorporate combinations of negative feedback control and cooperative stability in terms of eight systems characteristics pertaining to optimality, robustness and controllability. Intriguingly, though individual circuits prevailed for distinct characteristics, the system with cooperative stability alone achieved the most balanced performance across all characteristics. Our study provides theoretical justification for the contribution of cooperative stability to natural biological systems and represents a guideline for designing synthetic complex formation systems with desirable characteristics.
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spelling pubmed-92134652022-06-23 Cooperative stability renders protein complex formation more robust and controllable Hsu, Kuan-Lun Yen, Hsueh-Chi S. Yeang, Chen-Hsiang Sci Rep Article Protein complexes are the fundamental units of many biological functions. Despite their many advantages, one major adverse impact of protein complexes is accumulations of unassembled subunits that may disrupt other processes or exert cytotoxic effects. Synthesis of excess subunits can be inhibited via negative feedback control or they can be degraded more efficiently than assembled subunits, with this latter being termed cooperative stability. Whereas controlled synthesis of complex subunits has been investigated extensively, how cooperative stability acts in complex formation remains largely unexplored. To fill this knowledge gap, we have built quantitative models of heteromeric complexes with or without cooperative stability and compared their behaviours in the presence of synthesis rate variations. A system displaying cooperative stability is robust against synthesis rate variations as it retains high dimer/monomer ratios across a broad range of parameter configurations. Moreover, cooperative stability can alleviate the constraint of limited supply of a given subunit and makes complex abundance more responsive to unilateral upregulation of another subunit. We also conducted an in silico experiment to comprehensively characterize and compare four types of circuits that incorporate combinations of negative feedback control and cooperative stability in terms of eight systems characteristics pertaining to optimality, robustness and controllability. Intriguingly, though individual circuits prevailed for distinct characteristics, the system with cooperative stability alone achieved the most balanced performance across all characteristics. Our study provides theoretical justification for the contribution of cooperative stability to natural biological systems and represents a guideline for designing synthetic complex formation systems with desirable characteristics. Nature Publishing Group UK 2022-06-21 /pmc/articles/PMC9213465/ /pubmed/35729235 http://dx.doi.org/10.1038/s41598-022-14362-z Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Hsu, Kuan-Lun
Yen, Hsueh-Chi S.
Yeang, Chen-Hsiang
Cooperative stability renders protein complex formation more robust and controllable
title Cooperative stability renders protein complex formation more robust and controllable
title_full Cooperative stability renders protein complex formation more robust and controllable
title_fullStr Cooperative stability renders protein complex formation more robust and controllable
title_full_unstemmed Cooperative stability renders protein complex formation more robust and controllable
title_short Cooperative stability renders protein complex formation more robust and controllable
title_sort cooperative stability renders protein complex formation more robust and controllable
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9213465/
https://www.ncbi.nlm.nih.gov/pubmed/35729235
http://dx.doi.org/10.1038/s41598-022-14362-z
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