Moonlighting Proteins Some Hypotheses on the Structural Origin of Their Multifunctionality
Cedano Rodríguez, Juan Antonio (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Huerta Casado, Mario (University Hospital Heidelberg. Institute of Pathology)
Mozo-Villarias, Angel (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Querol Murillo, Enrique (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)

Date:	2025
Abstract:	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.
Grants:	Agencia Estatal de Investigación PID2021-125632OB-C22 Ministerio de Economía y Competitividad PID2024-159663OB-C21
Rights:	Aquest 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.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Moonlighting proteins ; Multitasking proteins ; Moonlighting proteins evolution ; Non-orthologous gene displacement ; Non-homologous isofunctional enzymes ; Fold-switching proteins ; Protein structure and function ; Conformational plasticity
Published in:	International journal of molecular sciences, Vol. 26, Num. 21 (November 2025) , art. 10375, ISSN 1422-0067

DOI: 10.3390/ijms262110375
PMID: 41226413

11 p, 741.3 KB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Biotecnologia i de Biomedicina (IBB)
Articles > Research articles
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