Group Leader/s

 

intro

GROUP

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. 

FIG1

fig1.1

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.

Superposition of A. vaginae and human liver GAPDH X-ray structures

 

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. 

FIG3

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. 

 

Cuervo A, Fàbrega-Ferrer M, Machón C, Conesa JJ, Fernández FJ, Pérez-Luque R, Pérez-Ruiz M, Pous J, Vega MC, Carrascosa JL, Coll M.  [2019]. Structures of T7 bacteriophage portal and tail suggest a viral DNA retention and ejection mechanism. Nat Comm 10(1):3746.

Fernández FJ, Gómez S, Vega MC  [2019]. High-Throughput Protein Production in Yeast. Methods in Molecular Biology. 2025, 69-91.

Gómez S, Fernández FJ, Vega MC  [2019]. High-Throughput Micro-Characterization of RNA–Protein Interaction. Methods in Molecular Biology. 2025, 519-531.

Gómez S, Navas-Yuste S, Payne AM, Rivera W, López-Estepa M, Brangbour C, Fullà D , Juanhuix J, Fernández FJ, Vega MC  [2019]. Peroxisomal catalases from the yeasts Pichia pastoris and Kluyveromyces lactis as models for oxidative damage in higher eukaryotes. Free Radic Biology and Biomedicine, 141, 279-290.

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  [2019]. 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  [2019]. Pathogens’ toolbox to manipulate human complement. Seminars Cell Dev Biol. 85, 98-109.

Regueiro JR, Fernández F, Vega MC  [2019]. Complement in leucocyte development and function. Seminars Cell Dev Biol 85, 84-85.

Fernández FJ, Gómez S, Navas-Yuste S, López-Estepa M, Vega MC  [2017]. Protein-tRNA Agarose Gel Retardation Assays for the Analysis of the N6-threonylcarbamoyladenosine TcdA Function. J Vis Exp 124.

 

Funding

Activación de la Vía Alternativa del Complemento y su Relevancia en la Enfermedad Renal por DD (RTI2018-102242-B-I00), MINECO
2019-2021
PI: M. Cristina Vega

El sistema de Complemento en Salud y Enfermedad (S2017/BMD-3673), Comunidad de Madrid
2018-2021

Complemento en Salud y Enfermedad (SAF2016-81876-REDT), Red de Excelencia, MINECO
2017-2019

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
2016-2018
PI: Fabrizio Martino

Healing complement C3-associated diseases (SAF2015-72961-EXP), EXPLORA Programme, MINECO
2017-2018
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
2016-2018
PI: M. Cristina Vega

Structural Biology of Host-Pathogen Interactions (20160E064), PIE Project, CSIC
2016-2019
PI: M. Cristina Vega

New Technologies and Production Tools for Complex Protein Biologics (ComplexINC 279039), FP7-HEALTH-2011, EU
2011-2016
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
2013-2016
PI: M. Cristina Vega

Biology and physiopathology of the complement system (S2010/BMD-2316)Comunidad de Madrid
2012-2015
PI: M. Cristina Vega

 

CSIC          Gobierno de España    Comunidad de MadridUE

 

 

 

Fellowships and jobs

 

More info

PRINCIPAL INVESTIGATOR

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.

Co-founder Abvance 

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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 > 69K downloads in mid 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).

 

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