Mercedes Spínola‐Amilibia

Centro de Investigaciones Biológicas Margarita Salas

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Jerónimo Bravo

University of Buenos Aires

Antonio Romero

Centro de Investigaciones Biológicas Margarita Salas

Ernesto Arias‐Palomo

Centro de Investigaciones Biológicas Margarita Salas

IÐ

Ivan Ðikić

Goethe University Frankfurt

Yonathan Lissanu Deribe

The University of Texas MD Anderson Cancer Center

Federico M. Ruiz

Centro de Investigaciones Biológicas Margarita Salas

Nayra Cárdenes

University of Pittsburgh

Gabriel Moncalián

Instituto de Biomedicina y Biotecnología de Cantabria

José Rivera

Universidad Europea de Madrid

José L. Neira

Universitat de Miguel Hernández d'Elx

Cooperative Institutions

Consejo Superior de Investigaciones Científicas

Centro de Investigaciones Biológicas Margarita Salas

Centro Nacional de Biotecnología

Universidad Complutense de Madrid

Spanish National Cancer Research Centre

Universidad Autónoma de Madrid

Institut de Biologia Molecular de Barcelona

Vrije Universiteit Brussel

VIB-VUB Center for Structural Biology

Vlaams Instituut voor Biotechnologie

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Estudios estructurales de BRMS1 y Tax1BP1, proteínas involucradas en la vía de activación de NFkB

Mercedes Spínola‐Amilibia

Metastasis is a life-threatening complication of cancer that represents 90% of cancer-related deaths. It is the process by which tumor cells disseminate from the primary tumor, migrate through the basement membrane, survive in the circulatory system, invade into a secondary site, and start to proliferate. This process is mainly developed by the de-regulation of vital pathways controlling the biological mecanism. One of them is the signalling pathway that mediate the activation of the NFkB transcription factor, a central coordinator of the immune response. It has become clear that NFkB signalling has a critical role in cancer development and progression. It also regulate tumour angiogenesis and invasiveness, being correlated with up-activation of the transcription factor level. Nowadays, the mayor goal has been to determine the molecular networks, looking at genes that induce or inhibit metastasis. For this reason, we focused on two negative regulators of NFkB pathway, which are, BRMS1 and Tax1BP1. Breast cancer metastasis suppressor (BRMS1) is a member of a functional family of genes known as metastasis suppressors that have the ability to inhibit the appearance of macroscopic metastases in breast, melanoma and ovarian tumours without affecting the growth of the primary tumour, by acting at different steps of the metastatic cascade. Very little is known about the molecular aspects of the antimetastatic properties of BRMS1, and therefore the structural characterization of BRMS1 can provide important information on the molecular mechanisms involved in this protein function. In the present study, we show the tridimensional structure of the first predicted coiled-coil motif of human BRMS1. In addition, it has been previously determined the participation of the N-terminal coiled-coil of this protein in interactions with some relevant proteins to cancer (Rivera et al., unpublished results). One of them is a co-factor of transcription, named NMI, N-Myc and STAT interactor protein. The rescued NMI fragment in a yeast to hibrid assay included the predicted coiled-coil motif. It is reported that coiled-coil regions are well known protein?protein interaction modules (Lupas, 1996), and for this reason, we selected this motif for structural sudies of the complex NMR and ITC expermiments shown that the two coiled-coil motif interact upon tested conditions. On the other hand, it is reported that ubiquitination regulates at least three steps in the NFkB pathway (Chen, 2005; Haglun y Dikic, 2005; Hoeller et. al., 2006). Tax1BP1 or Tax Binding Protein 1 is one of the proteins implicated in this process. The interaction between this protein and ubiquitn is through its carboxyl-terminal end, which contains two zinc finger domains (UBZ) (Iha et al., 2008). We obtain the tridimensional conformation of both domains, and we concluded that only UBZ2 appears to be a ubiquitin binding C2H2 zinc finger domain. The consesus sequence established in the UBD (Ubiquiten Binding Domains) is not conserved amongst UBZ1 and UBZ2, which suggests that the interaction with ubiquitin should take place in a different manner.

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The structure of VgrG1, the needle tip of the bacterial Type VI Secretion System

Mercedes Spínola‐Amilibia Irene Davó-Siguero Flávia Montanari Ruiz Elena Santillana Francisco J. Medrano

10.2210/pdb4uhv/pdb

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Correction: Crystal Structure of Hcp from Acinetobacter baumannii: A Component of the Type VI Secretion System

PLoS ONE (2015)

Federico M. Ruiz Elena Santillana Mercedes Spínola‐Amilibia Eva Torreira Esther Culebras

The following information is missing from the Funding section: This work was supported by FIS PI13/01471, BFU2011-24615 and CSD2009-00088 Spanish projects, and the Regional Government of Madrid (S2010/BMD-2353). F.M.R. was supported by an ESF/CSIC funded JAE-Doc Contract.

Acinetobacter baumannii

Component (thermodynamics)

10.1371/journal.pone.0136978

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Plastic degradation by insect hexamerins: Near-atomic resolution structures of the polyethylene-degrading proteins from the wax worm saliva

Science Advances (2023)

Mercedes Spínola‐Amilibia R. Illanes Elena Ruiz-López Pere Colomer-Vidal Francisco Rodríguez-Ventura

Plastic waste management is a pressing ecological, social, and economic challenge. The saliva of the lepidopteran Galleria mellonella larvae is capable of oxidizing and depolymerizing polyethylene in hours at room temperature. Here, we analyze by cryo-electron microscopy (cryo-EM) G. mellonella's saliva directly from the native source. The three-dimensional reconstructions reveal that the buccal secretion is mainly composed of four hexamerins belonging to the hemocyanin/phenoloxidase family, renamed Demetra, Cibeles, Ceres, and a previously unidentified factor termed Cora. Functional assays show that this factor, as its counterparts Demetra and Ceres, is also able to oxidize and degrade polyethylene. The cryo-EM data and the x-ray analysis from purified fractions show that they self-assemble primarily into three macromolecular complexes with striking structural differences that likely modulate their activity. Overall, these results establish the ground to further explore the hexamerins' functionalities, their role in vivo, and their eventual biotechnological application.

Degradation

10.1126/sciadv.adi6813

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Molecular basis for transposase activation by a dedicated AAA+ ATPase

Nature (2024)

Álvaro de la Gándara Mercedes Spínola‐Amilibia Lidia Araújo‐Bazán Rafael Núñez‐Ramírez James M. Berger

Abstract Transposases drive chromosomal rearrangements and the dissemination of drug-resistance genes and toxins 1–3 . Although some transposases act alone, many rely on dedicated AAA+ ATPase subunits that regulate site selectivity and catalytic function through poorly understood mechanisms. Using IS 21 as a model transposase system, we show how an ATPase regulator uses nucleotide-controlled assembly and DNA deformation to enable structure-based site selectivity, transposase recruitment, and activation and integration. Solution and cryogenic electron microscopy studies show that the IstB ATPase self-assembles into an autoinhibited pentamer of dimers that tightly curves target DNA into a half-coil. Two of these decamers dimerize, which stabilizes the target nucleic acid into a kinked S-shaped configuration that engages the IstA transposase at the interface between the two IstB oligomers to form an approximately 1 MDa transpososome complex. Specific interactions stimulate regulator ATPase activity and trigger a large conformational change on the transposase that positions the catalytic site to perform DNA strand transfer. These studies help explain how AAA+ ATPase regulators—which are used by classical transposition systems such as Tn7, Mu and CRISPR-associated elements—can remodel their substrate DNA and cognate transposases to promote function.

Transposase

Transposition (logic)

10.1038/s41586-024-07550-6

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Structure of the UBZ1and2 tandem of the ubiquitin-binding adaptor protein TAX1BP1

M. Angeles Ceregido Mercedes Spínola‐Amilibia L. Buts J. Rivera Jerónimo Bravo

Tandem

10.2210/pdb4bmj/pdb

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Wax worm saliva and the enzymes therein are the key to polyethylene degradation by Galleria mellonella

bioRxiv (Cold Spring Harbor Laboratory) (2022)

Anahí Sanluis‐Verdes Pere Colomer-Vidal Francisco Rodríguez-Ventura M. Bello-Villarino Mercedes Spínola‐Amilibia

ABSTRACT Plastic degradation by biological systems with re-utilization of the by-products can be the future solution to the global threat of plastic waste accumulation. We report that the saliva of Galleria mellonella larvae (wax worms) is capable of oxidizing and depolymerizing polyethylene (PE), one of the most produced and sturdy polyolefin-derived plastics. This effect is achieved after a few hours’ exposure at room temperature and physiological conditions (neutral pH). The wax worm saliva can indeed overcome the bottleneck step in PE biodegradation, that is the initial oxidation step. Within the saliva, we identified two enzymes that can reproduce the same effect. This is the first report of enzymes with this capability, opening up the way to new ground-breaking solutions for plastic waste management through bio-recycling/up-cycling.

Galleria mellonella

Oxidizing agent

Degradation

Polyolefin

10.1101/2022.04.08.487620

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IS21 family transposase cleaved donor complex traps two right-handed superhelical crossings

Nature Communications (2023)

Mercedes Spínola‐Amilibia Lidia Araújo‐Bazán Álvaro de la Gándara James M. Berger Ernesto Arias‐Palomo

Abstract Transposases are ubiquitous enzymes that catalyze DNA rearrangement events with broad impacts on gene expression, genome evolution, and the spread of drug-resistance in bacteria. Here, we use biochemical and structural approaches to define the molecular determinants by which IstA, a transposase present in the widespread IS 21 family of mobile elements, catalyzes efficient DNA transposition. Solution studies show that IstA engages the transposon terminal sequences to form a high-molecular weight complex and promote DNA integration. A 3.4 Å resolution structure of the transposase bound to transposon ends corroborates our biochemical findings and reveals that IstA self-assembles into a highly intertwined tetramer that synapses two supercoiled terminal inverted repeats. The three-dimensional organization of the IstA•DNA cleaved donor complex reveals remarkable similarities with retroviral integrases and classic transposase systems, such as Tn7 and bacteriophage Mu, and provides insights into IS 21 transposition.

Transposase

Integrases

Inverted repeat

Insertion sequence

Transposition (logic)

Lysogenic cycle

10.1038/s41467-023-38071-x

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Citations (2)

BRMS151–98 and BRMS151–84 Are Crystal Oligomeric Coiled Coils with Different Oligomerization States, Which Behave as Disordered Protein Fragments in Solution

Journal of Molecular Biology (2013)

Mercedes Spínola‐Amilibia José Rivera M. Ortiz-Lombardı́a Antonio Romero José L. Neira

Coiled coil

Nuclear export signal

Antiparallel (mathematics)

Intrinsically Disordered Proteins

10.1016/j.jmb.2013.03.005

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Citations (5)

The structure of VgrG1 fromPseudomonas aeruginosa, the needle tip of the bacterial type VI secretion system

Acta Crystallographica Section D Structural Biology (2015)

Mercedes Spínola‐Amilibia Irene Davó-Siguero Federico M. Ruiz Elena Santillana Francisco J. Medrano

The type VI secretion system (T6SS) is a mechanism that is commonly used by pathogenic bacteria to infect host cells and for survival in competitive environments. This system assembles on a core baseplate and elongates like a phage puncturing device; it is thought to penetrate the target membrane and deliver effectors into the host or competing bacteria. Valine-glycine repeat protein G1 (VgrG1) forms the spike at the tip of the elongating tube formed by haemolysin co-regulated protein 1 (Hcp1); it is structurally similar to the T4 phage (gp27)3-(gp5)3 puncturing complex. Here, the crystal structure of full-length VgrG1 from Pseudomonas aeruginosa is reported at a resolution of 2.0 Å, which through a trimeric arrangement generates a needle-like shape composed of two main parts, the head and the spike, connected via a small neck region. The structure reveals several remarkable structural features pointing to the possible roles of the two main segments of VgrG1: the head as a scaffold cargo domain and the β-roll spike with implications in the cell-membrane puncturing process and as a carrier of cognate toxins.

Puncturing

10.1107/s2059798315021142

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Citations (37)