The nonlinear cysteine redox dynamics in the i-space: A proteoform-centric theory of redox regulation
The post-translational redox regulation of protein function by cysteine oxidation controls diverse biological processes, from cell division to death. However, most current site-centric paradigms fail to capture the nonlinear and emergent nature of redox regulation in proteins with multiple cysteines...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-04-01
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| Series: | Redox Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231725000369 |
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| author | James N. Cobley Panagiotis N. Chatzinikolaou Cameron A. Schmidt |
| author_facet | James N. Cobley Panagiotis N. Chatzinikolaou Cameron A. Schmidt |
| author_sort | James N. Cobley |
| collection | DOAJ |
| description | The post-translational redox regulation of protein function by cysteine oxidation controls diverse biological processes, from cell division to death. However, most current site-centric paradigms fail to capture the nonlinear and emergent nature of redox regulation in proteins with multiple cysteines. Here, we present a proteoform-centric theory of redox regulation grounded in the i-space. The i-space encapsulates the theoretical landscape of all possible cysteine proteoforms. Using computational approaches, we quantify the vast size of the abstract i-space, revealing its scale-free architecture—elucidating the disproportionate influence of cysteine-rich proteins. We define mathematical rules governing cysteine proteoform dynamics. Their dynamics are inherently nonlinear, context-dependent, and fundamentally constrained by protein copy numbers. Monte Carlo simulations of the human protein PTP1B reveal extensive i-space sampling beyond site-centric models, supporting the “oxiform conjecture”. This conjecture posits that highly oxidised proteoforms, molecules bearing multiple oxidised cysteines, are central to redox regulation. In support, even 90%-reduced proteomes can house vast numbers of unique, potentially functioanlly diverse, oxiforms. This framework offers a transformative lens for understanding the redox biology of proteoforms. |
| format | Article |
| id | doaj-art-e21d8e1e941445b491ae8d0ac723404c |
| institution | Kabale University |
| issn | 2213-2317 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj-art-e21d8e1e941445b491ae8d0ac723404c2025-02-10T04:34:21ZengElsevierRedox Biology2213-23172025-04-0181103523The nonlinear cysteine redox dynamics in the i-space: A proteoform-centric theory of redox regulationJames N. Cobley0Panagiotis N. Chatzinikolaou1Cameron A. Schmidt2The University of Dundee, Dundee, Scotland, UK; Corresponding author.Aristotle University of Thessaloniki, Serres, GreeceCells and Systems Biology lab, ECU biology, USAThe post-translational redox regulation of protein function by cysteine oxidation controls diverse biological processes, from cell division to death. However, most current site-centric paradigms fail to capture the nonlinear and emergent nature of redox regulation in proteins with multiple cysteines. Here, we present a proteoform-centric theory of redox regulation grounded in the i-space. The i-space encapsulates the theoretical landscape of all possible cysteine proteoforms. Using computational approaches, we quantify the vast size of the abstract i-space, revealing its scale-free architecture—elucidating the disproportionate influence of cysteine-rich proteins. We define mathematical rules governing cysteine proteoform dynamics. Their dynamics are inherently nonlinear, context-dependent, and fundamentally constrained by protein copy numbers. Monte Carlo simulations of the human protein PTP1B reveal extensive i-space sampling beyond site-centric models, supporting the “oxiform conjecture”. This conjecture posits that highly oxidised proteoforms, molecules bearing multiple oxidised cysteines, are central to redox regulation. In support, even 90%-reduced proteomes can house vast numbers of unique, potentially functioanlly diverse, oxiforms. This framework offers a transformative lens for understanding the redox biology of proteoforms.http://www.sciencedirect.com/science/article/pii/S2213231725000369OxiformsRedox regulationI-spaceNonlinearCysteine proteoforms |
| spellingShingle | James N. Cobley Panagiotis N. Chatzinikolaou Cameron A. Schmidt The nonlinear cysteine redox dynamics in the i-space: A proteoform-centric theory of redox regulation Redox Biology Oxiforms Redox regulation I-space Nonlinear Cysteine proteoforms |
| title | The nonlinear cysteine redox dynamics in the i-space: A proteoform-centric theory of redox regulation |
| title_full | The nonlinear cysteine redox dynamics in the i-space: A proteoform-centric theory of redox regulation |
| title_fullStr | The nonlinear cysteine redox dynamics in the i-space: A proteoform-centric theory of redox regulation |
| title_full_unstemmed | The nonlinear cysteine redox dynamics in the i-space: A proteoform-centric theory of redox regulation |
| title_short | The nonlinear cysteine redox dynamics in the i-space: A proteoform-centric theory of redox regulation |
| title_sort | nonlinear cysteine redox dynamics in the i space a proteoform centric theory of redox regulation |
| topic | Oxiforms Redox regulation I-space Nonlinear Cysteine proteoforms |
| url | http://www.sciencedirect.com/science/article/pii/S2213231725000369 |
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