Laura Miguel-Romero

Instituto de Biomedicina de Valencia

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Alberto Marina

Instituto de Salud Carlos III

Patricia Casino

Instituto de Investigación de Enfermedades Raras

José R. Penadés

Imperial College London

Alfred Fillol-Salom

Imperial College London

John Chen

Flinders University

Eduardo P. C. Rocha

Institut Pasteur

Cristina Mideros-Mora

Consejo Superior de Investigaciones Científicas

Vicente Monedero

Instituto de Agroquímica y Tecnología de Alimentos

Alberto Marina

CIC bioGUNE

Nasser Alqurainy

University of Glasgow

Cooperative Institutions

Consejo Superior de Investigaciones Científicas

Instituto de Biomedicina de Valencia

University of Iowa

Centro de Investigación Biomédica en Red

Centre for Biomedical Network Research on Rare Diseases

University of Glasgow

Instituto de Salud Carlos III

Universidad de Zaragoza

Imperial College London

Universitat de València

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The closed conformation of the LDL receptor is destabilized by the low Ca⁺⁺ concentration but favored by the high Mg⁺⁺ concentration in the endosome

FEBS Letters (2015)

Juan Martínez‐Oliván Xabier Arias‐Moreno Ramón Hurtado‐Guerrero José Alberto Carrodeguas Laura Miguel-Romero

The LDL receptor (LDLR) internalizes LDL and VLDL particles. In the endosomes, it adopts a closed conformation important for recycling, by interaction of two modules of the ligand binding domain (LR4–5) and a β‐propeller motif. Here, we investigate by SPR the interactions between those two modules and the β‐propeller. Our results indicate that the two modules cooperate to bind the β‐propeller. The binding is favored by low pH and by high [Ca ++ ]. Our data show that Mg ++ , at high concentration in the endosome, favors the formation of the closed conformation by replacing the structuring effect of Ca ++ in LR5. We propose a sequential model of LDL release where formation of the close conformation follows LDL release.

10.1016/j.febslet.2015.10.014

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Citations (7)

MaeR response regulator bound to beryllium trifluoride

Laura Miguel-Romero Patricia Casino J.M. Landete Vicente Monedero ∥M. Geraldine Zuniga

10.2210/pdb5lwk/pdb

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The SrrAB two-component system regulates Staphylococcus aureus pathogenicity through redox sensitive cysteines

Proceedings of the National Academy of Sciences (2020)

Nitija Tiwari Marisa López-Redondo Laura Miguel-Romero Katarina Kulhánková Michael P. Cahill

Staphylococcus aureus infections can lead to diseases that range from localized skin abscess to life-threatening toxic shock syndrome. The SrrAB two-component system (TCS) is a global regulator of S. aureus virulence and critical for survival under environmental conditions such as hypoxic, oxidative, and nitrosative stress found at sites of infection. Despite the critical role of SrrAB in S. aureus pathogenicity, the mechanism by which the SrrAB TCS senses and responds to these environmental signals remains unknown. Bioinformatics analysis showed that the SrrB histidine kinase contains several domains, including an extracellular Cache domain and a cytoplasmic HAMP-PAS-DHp-CA region. Here, we show that the PAS domain regulates both kinase and phosphatase enzyme activity of SrrB and present the structure of the DHp-CA catalytic core. Importantly, this structure shows a unique intramolecular cysteine disulfide bond in the ATP-binding domain that significantly affects autophosphorylation kinetics. In vitro data show that the redox state of the disulfide bond affects S. aureus biofilm formation and toxic shock syndrome toxin-1 production. Moreover, with the use of the rabbit infective endocarditis model, we demonstrate that the disulfide bond is a critical regulatory element of SrrB function during S. aureus infection. Our data support a model whereby the disulfide bond and PAS domain of SrrB sense and respond to the cellular redox environment to regulate S. aureus survival and pathogenesis.

Histidine kinase

10.1073/pnas.1921307117

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Citations (64)

The malate sensing two-component system MaeKR is a non-canonical class of sensory complex for C4-dicarboxylates

Scientific Reports (2017)

Laura Miguel-Romero Patricia Casino José María Landete Vicente Monedero Manuel Zúñiga

Microbial colonization of different environments is enabled to a great extent by the plasticity of their sensory mechanisms, among them, the two-component signal transduction systems (TCS). Here, an example of TCS plasticity is presented: the regulation of L-malate catabolism via malic enzyme by MaeRK in Lactobacillales. MaeKR belongs to the citrate family of TCS as the Escherichia coli DcuSR system. We show that the Lactobacillus casei histidine-kinase MaeK is defective in autophosphorylation activity as it lacks a functional catalytic and ATP binding domain. The cognate response regulator MaeR was poorly phosphorylated at its phosphoacceptor Asp in vitro. This phosphorylation, however, enhanced MaeR binding in vitro to its target sites and it was required for induction of regulated genes in vivo. Elucidation of the MaeR structure revealed that response regulator dimerization is accomplished by the swapping of α4-β5-α5 elements between two monomers, generating a phosphoacceptor competent conformation. Sequence and phylogenetic analyses showed that the MaeKR peculiarities are not exclusive to L. casei as they are shared by the rest of orthologous systems of Lactobacillales. Our results reveal MaeKR as a non-canonical TCS displaying distinctive features: a swapped response regulator and a sensor histidine kinase lacking ATP-dependent kinase activity.

Response regulator

Histidine kinase

Two-component regulatory system

10.1038/s41598-017-02900-z

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Citations (6)

MaeR D54A mutant response regulator bound to sulfate

Laura Miguel-Romero Patricia Casino J.M. Landete Vicente Monedero ∥M. Geraldine Zuniga

Response regulator

10.2210/pdb5lwl/pdb

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Beyond the CRISPR-Cas safeguard: PICI-encoded innate immune systems protect bacteria from bacteriophage predation

Current Opinion in Microbiology (2020)

Alfred Fillol-Salom Laura Miguel-Romero Alberto Marina John Chen José R. Penades

10.1016/j.mib.2020.06.002

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Citations (36)

Tail assembly interference is a common strategy in bacterial antiviral defenses

Nature Communications (2024)

Lingchen He Laura Miguel-Romero Jonasz B. Patkowski Nasser Alqurainy Eduardo P. C. Rocha

Many bacterial immune systems recognize phage structural components to activate antiviral responses, without inhibiting the function of the phage component. These systems can be encoded in specific chromosomal loci, known as defense islands, and in mobile genetic elements such as prophages and phage-inducible chromosomal islands (PICIs). Here, we identify a family of bacterial immune systems, named Tai (for 'tail assembly inhibition'), that is prevalent in PICIs, prophages and P4-like phage satellites. Tai systems protect their bacterial host population from other phages by blocking the tail assembly step, leading to the release of tailless phages incapable of infecting new hosts. To prevent autoimmunity, some Tai-positive phages have an associated counter-defense mechanism that is expressed during the phage lytic cycle and allows for tail formation. Interestingly, the Tai defense and counter-defense genes are organized in a non-contiguous operon, enabling their coordinated expression.

10.1038/s41467-024-51915-4

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Citations (3)

Conformational dynamism for DNA interaction in the Salmonella RcsB response regulator

Nucleic Acids Research (2017)

Patricia Casino Laura Miguel-Romero J. Huesa Pablo D. García Francisco García‐del Portillo

The RcsCDB phosphorelay system controls an extremely large regulon in Enterobacteriaceae that involves processes such as biofilm formation, flagella production, synthesis of extracellular capsules and cell division. Therefore, fine-tuning of this system is essential for virulence in pathogenic microorganisms of this group. The final master effector of the RcsCDB system is the response regulator (RR) RcsB, which activates or represses multiple genes by binding to different promoter regions. This regulatory activity of RcsB can be done alone or in combination with additional transcriptional factors in phosphorylated or dephosphorylated states. The capacity of RcsB to interact with multiple promoters and partners, either dephosphorylated or phosphorylated, suggests an extremely conformational dynamism for this RR. To shed light on the activation mechanism of RcsB and its implication on promoter recognition, we solved the crystal structure of full-length RcsB from Salmonella enterica serovar Typhimurium in the presence and absence of a phosphomimetic molecule BeF3−. These two novel structures have guided an extensive site-directed mutagenesis study at the structural and functional level that confirms RcsB conformational plasticity and dynamism. Our data allowed us to propose a β5-T switch mechanism where phosphorylation is coupled to alternative DNA binding ways and which highlights the conformational dynamism of RcsB to be so pleiotropic.

Response regulator

10.1093/nar/gkx1164

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Citations (19)

Structural and Functional Insights into Endoglin Ligand Recognition and Binding

PLoS ONE (2012)

Aaron Alt Laura Miguel-Romero Jordi Donderis Mikel Aristorena Francisco J. Blanco

Endoglin, a type I membrane glycoprotein expressed as a disulfide-linked homodimer on human vascular endothelial cells, is a component of the transforming growth factor (TGF)-β receptor complex and is implicated in a dominant vascular dysplasia known as hereditary hemorrhagic telangiectasia as well as in preeclampsia. It interacts with the type I TGF-β signaling receptor activin receptor-like kinase (ALK)1 and modulates cellular responses to Bone Morphogenetic Protein (BMP)-9 and BMP-10. Structurally, besides carrying a zona pellucida (ZP) domain, endoglin contains at its N-terminal extracellular region a domain of unknown function and without homology to any other known protein, therefore called the orphan domain (OD). In this study, we have determined the recognition and binding ability of full length ALK1, endoglin and constructs encompassing the OD to BMP-9 using combined methods, consisting of surface plasmon resonance and cellular assays. ALK1 and endoglin ectodomains bind, independently of their glycosylation state and without cooperativity, to different sites of BMP-9. The OD comprising residues 22 to 337 was identified among the present constructs as the minimal active endoglin domain needed for partner recognition. These studies also pinpointed to Cys350 as being responsible for the dimerization of endoglin. In contrast to the complete endoglin ectodomain, the OD is a monomer and its small angle X-ray scattering characterization revealed a compact conformation in solution into which a de novo model was fitted.

Ectodomain

10.1371/journal.pone.0029948

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Citations (98)

Non-canonical Staphylococcus aureus pathogenicity island repression

Nucleic Acids Research (2022)

Laura Miguel-Romero Mohammed Alqasmi Julio Bacarizo Jason A Tan Richard J. Cogdell

Abstract Mobile genetic elements control their life cycles by the expression of a master repressor, whose function must be disabled to allow the spread of these elements in nature. Here, we describe an unprecedented repression-derepression mechanism involved in the transfer of Staphylococcus aureus pathogenicity islands (SaPIs). Contrary to the classical phage and SaPI repressors, which are dimers, the SaPI1 repressor StlSaPI1 presents a unique tetrameric conformation never seen before. Importantly, not just one but two tetramers are required for SaPI1 repression, which increases the novelty of the system. To derepress SaPI1, the phage-encoded protein Sri binds to and induces a conformational change in the DNA binding domains of StlSaPI1, preventing the binding of the repressor to its cognate StlSaPI1 sites. Finally, our findings demonstrate that this system is not exclusive to SaPI1 but widespread in nature. Overall, our results characterize a novel repression-induction system involved in the transfer of MGE-encoded virulence factors in nature.

Derepression

Pathogenicity island

10.1093/nar/gkac855

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Citations (7)