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Updated: Oct 30, 2025

Phage Phenomics: Physiological Approaches to Characterize Novel Viral Proteins
Published on: June 11, 2015
Pathogen Moonlighting Proteins: From Ancestral Key Metabolic Enzymes to Virulence Factors
Luis Franco-Serrano1, David Sánchez-Redondo1, Araceli Nájar-García1
1Institut de Biotecnologia i Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Cerdanyola del Vallés, 08193 Barcelona, Spain.
Abstract:
Moonlighting and multitasking proteins refer to proteins with two or more functions performed by a single polypeptide chain. An amazing example of the Gain of Function (GoF) phenomenon of these proteins is that 25% of the moonlighting functions of our Multitasking Proteins Database (MultitaskProtDB-II) are related to pathogen virulence activity. Moreover, they usually have a canonical function belonging to highly conserved ancestral key functions, and their moonlighting functions are often involved in inducing extracellular matrix (ECM) protein remodeling. There are three main questions in the context of moonlighting proteins in pathogen virulence: (A) Why are a high percentage of pathogen moonlighting proteins involved in virulence? (B) Why do most of the canonical functions of these moonlighting proteins belong to primary metabolism? Moreover, why are they common in many pathogen species? (C) How are these different protein sequences and structures able to bind the same set of host ECM protein targets, mainly plasminogen (PLG), and colonize host tissues? By means of an extensive bioinformatics analysis, we suggest answers and approaches to these questions. There are three main ideas derived from the work: first, moonlighting proteins are not good candidates for vaccines. Second, several motifs that might be important in the adhesion to the ECM were identified. Third, an overrepresentation of GO codes related with virulence in moonlighting proteins were seen.
Insights
Moonlighting proteins, performing multiple functions, are key in pathogen virulence by remodeling host tissues. Bioinformatics analysis reveals specific motifs for ECM adhesion but suggests these proteins are poor vaccine candidates.
Area of Science:
- Molecular Biology
- Bioinformatics
- Pathogen Biology
Background:
- Moonlighting proteins possess multiple functions within a single polypeptide chain.
- A significant portion (25%) of known moonlighting proteins are implicated in pathogen virulence.
- These proteins often have conserved canonical functions in primary metabolism and contribute to extracellular matrix (ECM) remodeling.
Purpose of the Study:
- To investigate the prevalence and mechanisms of moonlighting proteins in pathogen virulence.
- To address why moonlighting proteins are frequently involved in virulence and associated with primary metabolism.
- To understand how diverse moonlighting proteins bind host ECM targets like plasminogen (PLG) for tissue colonization.
Main Methods:
- Extensive bioinformatics analysis of moonlighting proteins.
- Identification of conserved motifs involved in host-pathogen interactions.
- Gene Ontology (GO) enrichment analysis.
Main Results:
- Identified several motifs potentially involved in ECM adhesion.
- Observed an overrepresentation of Gene Ontology (GO) codes related to virulence in moonlighting proteins.
- Found that moonlighting proteins are not ideal candidates for vaccine development.
Conclusions:
- Moonlighting proteins play a crucial role in pathogen virulence through ECM remodeling and host tissue colonization.
- Specific sequence motifs facilitate binding to host ECM proteins, particularly plasminogen.
- The study provides insights into the evolutionary and functional significance of moonlighting proteins in infectious diseases.
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