Moonlighting Proteins

Moonlighting proteins-single polypeptides performing multiple, often unrelated functions-are increasingly recognized as key players in human disease and microbial pathogenesis, making their identification crucial for understanding disease mechanisms and developing targeted therapies. This study addr...

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Autores: Cedano, Juan|||0000-0003-1380-8036, Huerta Casado, Mario, Mozo-Villarias, Angel|||0000-0001-6559-7926, Querol Murillo, Enrique|||0000-0002-3658-3434
Tipo de recurso: artículo
Fecha de publicación:2025
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:322562
Acceso en línea:https://ddd.uab.cat/record/322562
https://dx.doi.org/urn:doi:10.3390/ijms262110375
Access Level:acceso abierto
Palabra clave:Moonlighting proteins
Multitasking proteins
Moonlighting proteins evolution
Non-orthologous gene displacement
Non-homologous isofunctional enzymes
Fold-switching proteins
Protein structure and function
Conformational plasticity
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spelling Moonlighting ProteinsSome Hypotheses on the Structural Origin of Their MultifunctionalityCedano, Juan|||0000-0003-1380-8036Huerta Casado, MarioMozo-Villarias, Angel|||0000-0001-6559-7926Querol Murillo, Enrique|||0000-0002-3658-3434Moonlighting proteinsMultitasking proteinsMoonlighting proteins evolutionNon-orthologous gene displacementNon-homologous isofunctional enzymesFold-switching proteinsProtein structure and functionConformational plasticityMoonlighting proteins-single polypeptides performing multiple, often unrelated functions-are increasingly recognized as key players in human disease and microbial pathogenesis, making their identification crucial for understanding disease mechanisms and developing targeted therapies. This study addresses the unresolved question of how such multifunctionality evolves, focusing on two potential structural mechanisms: Non-Orthologous Gene Displacement/Non-Homologous Isofunctional Enzymes (NOGD/NHIE), where evolutionarily unrelated proteins perform the same function, and Fold-Switching Proteins (FSP), which adopt alternative secondary structures to switch functions without sequence changes. We analyzed the overlap between known human moonlighting proteins (from MultitaskProtDB-II) and curated datasets of NOGD/NHIE (Non-Orthologous Gene Displacement/Non-Homologous Isofunctional Enzymes) and fold-switching proteins (FSPs), using Fisher's exact test for statistical validation. Moonlighting proteins showed extraordinary enrichment for NOGD/NHIE (19.89% vs. 0.39% in non-moonlighting proteins; odds ratio = 63.1, p < 2.2 × 10 -16) and strong enrichment for FSPs (6.99% vs. 0.26%; odds ratio = 28.7, p = 1.13 × 10 -14), corresponding to ~51-fold and ~27-fold higher risks, respectively. These findings establish intrinsic structural plasticity-whether through evolutionary replacement (NOGD/NHIE) or conformational switching (FSP)-as a central mechanism enabling functional moonlighting in the human proteome. The results suggest that such plasticity facilitates functional innovation while preserving sequence integrity, and that both NOGD/NHIE and FSP features may serve as predictive signatures for identifying novel moonlighting proteins, particularly those with implications for disease mechanisms and therapeutic targeting. 22025-01-0120252025-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/322562https://dx.doi.org/urn:doi:10.3390/ijms262110375reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengAgencia Estatal de Investigación https://doi.org/10.13039/501100011033 PID2021-125632OB-C22Ministerio de Economía y Competitividad https://doi.org/10.13039/501100003329 PID2024-159663OB-C21open accesshttp://purl.org/coar/access_right/c_abf2Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:3225622026-06-06T12:50:31Z
dc.title.none.fl_str_mv Moonlighting Proteins
Some Hypotheses on the Structural Origin of Their Multifunctionality
title Moonlighting Proteins
spellingShingle Moonlighting Proteins
Cedano, Juan|||0000-0003-1380-8036
Moonlighting proteins
Multitasking proteins
Moonlighting proteins evolution
Non-orthologous gene displacement
Non-homologous isofunctional enzymes
Fold-switching proteins
Protein structure and function
Conformational plasticity
title_short Moonlighting Proteins
title_full Moonlighting Proteins
title_fullStr Moonlighting Proteins
title_full_unstemmed Moonlighting Proteins
title_sort Moonlighting Proteins
dc.creator.none.fl_str_mv Cedano, Juan|||0000-0003-1380-8036
Huerta Casado, Mario
Mozo-Villarias, Angel|||0000-0001-6559-7926
Querol Murillo, Enrique|||0000-0002-3658-3434
author Cedano, Juan|||0000-0003-1380-8036
author_facet Cedano, Juan|||0000-0003-1380-8036
Huerta Casado, Mario
Mozo-Villarias, Angel|||0000-0001-6559-7926
Querol Murillo, Enrique|||0000-0002-3658-3434
author_role author
author2 Huerta Casado, Mario
Mozo-Villarias, Angel|||0000-0001-6559-7926
Querol Murillo, Enrique|||0000-0002-3658-3434
author2_role author
author
author
dc.subject.none.fl_str_mv Moonlighting proteins
Multitasking proteins
Moonlighting proteins evolution
Non-orthologous gene displacement
Non-homologous isofunctional enzymes
Fold-switching proteins
Protein structure and function
Conformational plasticity
topic Moonlighting proteins
Multitasking proteins
Moonlighting proteins evolution
Non-orthologous gene displacement
Non-homologous isofunctional enzymes
Fold-switching proteins
Protein structure and function
Conformational plasticity
description Moonlighting proteins-single polypeptides performing multiple, often unrelated functions-are increasingly recognized as key players in human disease and microbial pathogenesis, making their identification crucial for understanding disease mechanisms and developing targeted therapies. This study addresses the unresolved question of how such multifunctionality evolves, focusing on two potential structural mechanisms: Non-Orthologous Gene Displacement/Non-Homologous Isofunctional Enzymes (NOGD/NHIE), where evolutionarily unrelated proteins perform the same function, and Fold-Switching Proteins (FSP), which adopt alternative secondary structures to switch functions without sequence changes. We analyzed the overlap between known human moonlighting proteins (from MultitaskProtDB-II) and curated datasets of NOGD/NHIE (Non-Orthologous Gene Displacement/Non-Homologous Isofunctional Enzymes) and fold-switching proteins (FSPs), using Fisher's exact test for statistical validation. Moonlighting proteins showed extraordinary enrichment for NOGD/NHIE (19.89% vs. 0.39% in non-moonlighting proteins; odds ratio = 63.1, p < 2.2 × 10 -16) and strong enrichment for FSPs (6.99% vs. 0.26%; odds ratio = 28.7, p = 1.13 × 10 -14), corresponding to ~51-fold and ~27-fold higher risks, respectively. These findings establish intrinsic structural plasticity-whether through evolutionary replacement (NOGD/NHIE) or conformational switching (FSP)-as a central mechanism enabling functional moonlighting in the human proteome. The results suggest that such plasticity facilitates functional innovation while preserving sequence integrity, and that both NOGD/NHIE and FSP features may serve as predictive signatures for identifying novel moonlighting proteins, particularly those with implications for disease mechanisms and therapeutic targeting.
publishDate 2025
dc.date.none.fl_str_mv 2
2025-01-01
2025
2025-01-01
dc.type.none.fl_str_mv Article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://ddd.uab.cat/record/322562
https://dx.doi.org/urn:doi:10.3390/ijms262110375
url https://ddd.uab.cat/record/322562
https://dx.doi.org/urn:doi:10.3390/ijms262110375
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 PID2021-125632OB-C22
Ministerio de Economía y Competitividad https://doi.org/10.13039/501100003329 PID2024-159663OB-C21
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Dipòsit Digital de Documents de la UAB
instname:Universitat Autònoma de Barcelona
instname_str Universitat Autònoma de Barcelona
reponame_str Dipòsit Digital de Documents de la UAB
collection Dipòsit Digital de Documents de la UAB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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