The Structural Biology of Host-Pathogen Interactions group focuses in the understanding of the protein-protein interactions that mediate the communication between human beings and the bacterial communities to which we are continuously exposed. These interactions often involve bacterial pathogens, which attempt to evade the constant surveillance of human innate immunity and, specifically, the activated branch of the complement system. Our group studies other processes that are vital for bacterial cell survival in the human body as well as in environmental pools, including enzymes of the sugar and amino acid metabolism and sulfur mobilisation and trafficking. To this aim, we use a combination of advanced protein production techniques, X-ray diffraction, biochemical, biophysical, and computational chemistry methods to analyse snapshots of the protein complex interactions as well as their associated dynamic behavior, both of which underlie the functional outcomes of those interactions.
As a result of our participation in the European ComplexINC and the Complemento I (CM) consortia, we have recently co-founded a start-up biopharmaceutical company, Abvance, to deliver innovative antibody-based medicines for the treatment of immune disorders, inflammatory and neurodegenerative diseases.
Complement system of the innate immunity
The interactions that occur at the interface between the human host and the myriad bacterial microorganisms with which we come into daily contact constitute a topic of profound significance, both at a fundamental biological level and as an area of expanding medical interest. The complement system of the innate immunity stands as one of the first defence barriers against pathogens. It is a collection of soluble and membrane-associated proteins that monitor the blood and tissue interstitial fluids for pathogens, apoptotic cells and immune complexes. Pathogens have evolved sophisticated molecular weaponry that allows them to escape surveillance from the complement system, a strategy designated as immunoevasion. In this context, we are focused in elucidating the structures and mechanistic details of the complement system components and their protein complexes with virulence factors with immunoevasive properties.
GAPDH, an essential glycolytic enzyme central to carbon and energy metabolism, stands as a highly interesting moonlighting protein with the capacity to function as a virulence factor. In this pathogenic role, GAPDH can bind to several human complement factors thereby interfering with the natural defence barriers put forth by the human innate immunity. Our group has contributed to establishing the immunoevasive role of bacterial GAPDH among various Gram-positive pathogens (e.g. S. pyogenes, A. vaginae, C. perfringens) (Querol et al. 2018, 2019). These studies have paved the way for the discovery of novel antimicrobial agents designed to disrupt the interaction between GAPDH and the anaphylatoxin C5a and C3. Increasing our understanding of these processes at the atomic level is crucial for the development of potential treatments against bacterial infectious diseases.
Improving Methods for Production of Therapeutic Molecules
We are interested in the development and improvement of new technologies and production tools for complex protein biologics using yeast expression methodologies and other eukaryotic expression systems. Our group was a member of the FP7 Project ComplexINC, which conceptualised and systematically generated advanced toolkits to enable high-throughput assembly of complex biologics and metabolic pathways using eukaryotic expression systems. The ultimate goal of these toolkits, including two yeast-based toolkits developed in our laboratory, was enabling micro- and large-scale production of high-quality protein biologics for drug discovery and as biotherapeutics.
Metabolism of carbohydrates and amino acids
The extensive metabolic network that supports bacterial and fungal organisms and communities (commensal and pathogenic) contains an impressive repertoire of enzymes capable of synthesizing and metabolizing amino acids, carbohydrates and sulfur.
Carbohydrate active enzymes are enzymes capable of synthesising or breaking glycosidic bonds as well as the non-catalytic carbohydrate binding modules (CBMs) that frequently are associated with the active enzymes. Sugar metabolic enzyme is a wider term describing any enzyme which recognises, binds and modifies sugar molecules, usually within the context of a biochemical pathway. Carbohydrate active and sugar metabolic enzymes are also relevant enzymes for biotechnological applications, including the biofuel industry, as well as for the analysis of plant-fungi interactions owing to the widespread use of extracellular glycosyl hydrolases by plant pathogenic fungi.
Sulfur trafficking is important for the celular fitness and organisms have evolved complex systems of interacting proteins with the task of mobilising sulfur atoms from the amino acid L-cysteine in the form of highly reactive persulfides (-S-S–). The destination — iron-sulfur (Fe-S) clusters, sulfur-containing vitamins, cofactors and lipids, or thiol-containing tRNA hypermodified ribonucleosides. Our research has focused on the minimalistic CSD (Cysteine Sulfinate Desulfinase) system of the model bacterium E. coli, with 3 components which encodes a cysteine desulfurase or sulfur donor (CsdA), a sulfur acceptor (CsdE), and TcdA, an E1-like enzyme capable of cyclising the N6-threonylcarbamoyl adenosine (t6A) present at the A37 position of the anti-codon stem loop (ASL) motif of tRNA(ANN) molecules.
We have established a novel mechanism for the transfer of sulfur atoms across protein-protein interfaces and have deciphered the role of the conserved Cys loop motifs present both in CsdA and type II Cys-desulfurases like SufS. We have also pursued the connection between sulfur trafficking via the CSD system with tRNA biology through TcdA, the enzyme responsible for the synthesis of "cyclic t6A" (ct6A) in bacteria, protists, fungi and plants, where it ensures the fidelity and efficiency of translation.
Gómez S, Querol-García J, Sánchez-Barrón G, Subías M, González-Alsina A, Franco-Hidalgo V, Albertí S, Rodríguez de Córdoba S, Fernández FJ, Vega MC . The Antimicrobials Anacardic Acid and Curcumin are Not-Competitive Inhibitors of Gram-positive Bacterial Pathogenic Glyceraldehyde-3-phosphate Dehydrogenase by a Mechanism Unrelated to Human C5a Anaphylatoxin Binding. Front Microbiol 10:326.
Fernández FJ, Gómez S, Vega MC . Pathogens’ toolbox to manipulate human complement. Seminars Cell Dev Biol. 85, 98-109.
Regueiro JR, Fernández F, Vega MC . Complement in leucocyte development and function. Seminars Cell Dev Biol 85, 84-85.
Herrera-Morandé A, Castro-Fernández V, Merino F, Ramírez-Sarmiento C, Fernández FJ, Vega MC*, Guixé V* [2018 ]. Protein topology determines substrate-binding mechanism in homologous enzymes. Biochimica et Biophysica Acta (BBA) 1862(12), 2869-2878.
Peña-Soler E, Aranda J, López-Estepa M, Gómez S, Garces F, Coll M, Fernández FJ, Tuñón I, Vega MC . Insights into the inhibited form of the redox-sensitive SufE- like sulfur acceptor CsdE. PLoS ONE 12(10): e0186286.
Fernández FJ, Gómez S, Navas-Yuste S, López-Estepa M, Vega MC . Protein-tRNA Agarose Gel Retardation Assays for the Analysis of the N6-threonylcarbamoyladenosine TcdA Function. J Vis Exp 124.
Querol-García J, Fernández FJ, Marin AV, Gómez S, Fullà D, Melchor-Tafur C, Franco-Hidalgo V, Albertí S, Juanhuix J, Rodríguez de Córdoba S, Regueiro JR, Vega MC. . Crystal Structure of Glyceraldehyde-3-Phosphate Dehydrogenase from the Gram-Positive Bacterial Pathogen A. vaginae, an Immunoevasive Factor that Interacts with the Human C5a Anaphylatoxin. Front Microbiol 8:541.
Gómez S, López-Estepa M, Fernández FJ, Suárez T, Vega MC . Alternative Eukaryotic Expression Systems for the Production of Proteins and Protein Complexes. Adv Exp Med Biol. 2016;896:167-84.
Gómez S, López-Estepa M, Fernández FJ, Vega MC . Protein Complex production in Alternative Prokaryotic Hosts. Adv Exp Med Biol. 2016;896:115-33.
Fernández FJ, Ardá A, López-Estepa M, Aranda J, Peña-Soler E, Garces F, Round A, Campos-Olivas R, Bruix M, Coll M, Tuñón I, Jiménez-Barbero J, and Vega MC . Mechanism of Sulfur Transfer Across Protein-Protein Interfaces: The Cysteine Desulfurase Model System. ACS Catalysis 6(6), 3975-3984.
El sistema de Complemento en Salud y Enfermedad (S2017/BMD-3673), Comunidad de Madrid
Complemento en Salud y Enfermedad (SAF2016-81876-REDT), Red de Excelencia, MINECO
Caracterización Bioquímica, Estructural y funcional del supresor de tumores p51 binding protein 1 (TP53BP1) (SAF2014-59993-JIN), Proyectos I+D+i para Jóvenes Investigadores, MINECO
PI: Fabrizio Martino
Healing complement C3-associated diseases (SAF2015-72961-EXP), EXPLORA Programme, MINECO
PI: M. Cristina Vega
Development of new glycostructures with anti-infectious activity: Gram-positive bacteria and Dengue virus (CTQ2015-66206-C2-2-R), RETOS Programme, MINECO
PI: M. Cristina Vega
Structural Biology of Host-Pathogen Interactions (20160E064), PIE Project, CSIC
PI: M. Cristina Vega
New Technologies and Production Tools for Complex Protein Biologics (ComplexINC 279039), FP7-HEALTH-2011, EU
PI: M. Cristina Vega
Molecular structural basis of the dense deposit disease (DDD) caused by mutation in C3 and therapeutic opportunities (PI-121667), FIS, ISCIII
PI: M. Cristina Vega
Biology and physiopathology of the complement system (S2010/BMD-2316), Comunidad de Madrid
PI: M. Cristina Vega
Vega, María Cristina
B.Sc. 1992 in Organic Chemistry Dpt. of the Chemistry Faculty (UB) in Barcelona.
Ph.D. 1997 in Structural Biology from UPC and CID-CSIC in Barcelona.
Postdoctoral fellow at EMBL-Heidelberg and EMBL-Hamburg, Germany.
Ramón y Cajal scientist in 2004 at IBMB-CSIC.
Group Leader at CIB-CSIC since 2008.
Books and collections
- Edition of a new book on advanced methodologies for protein complex production using a variety of expression hosts and systems, which was published by Springer in spring of 2016. With > 60K downloads in early 2019, the volume is entitled Advanced Technologies for Protein Complex Production and Characterization and belongs in the Advances in Experimental Medicine and Biology (vol 896).
- Co-edition of a special volume in Seminars in Cell and Development with Prof. JR Regueiro entitled "Complement in Leucocyte Development and Function" (vol 85).