Institute Biomedicina Of Valencia

Valencia de Alcántara, Spain

Institute Biomedicina Of Valencia

Valencia de Alcántara, Spain

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Calvete J.J.,Institute Biomedicina Of Valencia
Biochemical Journal | Year: 2017

Venoms are integrated phenotypes that evolved independently in, and are used for predatory and defensive purposes by, a wide phylogenetic range of organisms. The same principles that contribute to the evolutionary success of venoms, contribute to making the study of venoms of great interest in such diverse fields as evolutionary ecology and biotechnology. Evolution is profoundly contingent, and nature also reinvents itself continuosly. Changes in a complex phenotypic trait, such as venom, reflect the influences of prior evolutionary history, chance events, and selection. Reconstructing the natural history of venoms, particularly those of snakes, which will be dealt with in more detail in this review, requires the integration of different levels of knowledge into a meaningful and comprehensive evolutionary framework for separating stochastic changes from adaptive evolution. The application of omics technologies and other disciplines have contributed to a qualitative and quantitative advance in the road map towards this goal. In this review we will make a foray into the world of animal venoms, discuss synergies and complementarities of the different approaches used in their study, and identify current bottlenecks that prevent inferring the evolutionary mechanisms and ecological constraints that molded snake venoms to their present-day variability landscape. © 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.


Calvete J.J.,Institute Biomedicina Of Valencia
Expert Review of Proteomics | Year: 2011

This article covers the application of proteomic tools ('venomics', 'antivenomics' and 'venom phenotyping') to study the composition and natural history of snake venoms, and the cross-reactivity of antivenoms with homologous and heterologous venoms, to help address the neglected pathology of snake bite envenoming. The identification of evolutionary and immunological trends may help to replace the traditional geographic- and phylogenetic-driven hypotheses for antivenom production strategies with a more rational approach based on proteome phenotype and immunological profile similarities. Antivenomics and venom phenotyping may also contribute to expand the clinical range of currently existing antidotes. © 2011 Expert Reviews Ltd.


Marin I.,Institute Biomedicina Of Valencia
BMC Evolutionary Biology | Year: 2010

Background. The patterns of emergence and diversification of the families of ubiquitin ligases provide insights about the evolution of the eukaryotic ubiquitination system. U-box ubiquitin ligases (UULs) are proteins characterized by containing a peculiar protein domain known as U box. In this study, the origin of the animal UUL genes is described. Results. Phylogenetic and structural data indicate that six of the seven main UUL-encoding genes found in humans (UBE4A, UBE4B, UIP5, PRP19, CHIP and CYC4) were already present in the ancestor of all current metazoans and the seventh (WDSUB1) is found in placozoans, cnidarians and bilaterians. The fact that only 4 - 5 genes orthologous to the human ones are present in the choanoflagellate Monosiga brevicollis suggests that several animal-specific cooptions of the U box to generate new genes occurred. Significantly, Monosiga contains five additional UUL genes that are not present in animals. One of them is also present in distantly-related protozoans. Along animal evolution, losses of UUL-encoding genes are rare, except in nematodes, which lack three of them. These general patterns are highly congruent with those found for other two families (RBR, HECT) of ubiquitin ligases. Conclusions. Finding that the patterns of emergence, diversification and loss of three unrelated families of ubiquitin ligases (RBR, HECT and U-box) are parallel indicates that there are underlying, linage-specific evolutionary forces shaping the complexity of the animal ubiquitin system. © 2010 Marín; licensee BioMed Central Ltd.


Marin I.,Institute Biomedicina Of Valencia
Molecular Biology and Evolution | Year: 2010

In a previous work, we characterized a gene, called Gypsy Integrase 1 (GIN1), which encodes a protein very similar to the integrase domains present in Gypsy/Ty3 retrotransposons. I describe here a paralog of GIN1 and GIN2 and show that both genes are present in multiple vertebrates and that a likely homolog is found in urochordates. Surprisingly, phylogenetic and structural analyses support the counterintuitive idea that the GIN genes did not directly derive from retrotransposons but from a novel type of animal-specific DNA transposons, the GIN elements. These elements, described for the first time in this study, are characterized by containing a gene that encodes a protein that is also very similar to Gypsy/Ty3 integrases. It turns out that the sequences of the integrases encoded by GIN1 and GIN2 are more similar to those found in GIN elements than to those detected in retrotransposons. Moreover, several introns are in the same positions in the integrase-encoding genes of some GIN elements, GIN1 and GIN2. The simplest explanation for these results is that GIN elements appeared early in animal evolution by co-option of the integrase of a retrotransposon, they later expanded in multiple animal lineages, and, eventually, gave rise to the GIN genes. In summary, GIN transposons may be the "missing link" that explain how GIN genes evolved from retrotransposons. GIN1 and GIN2 may have contributed to control the expansion of GIN elements and Gypsy/Ty3 retrotransposons in chordates. © The Author 2010. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved.


Marin I.,Institute Biomedicina Of Valencia
BMC Evolutionary Biology | Year: 2010

Background. HECT ubiquitin ligases (HECT E3s) are key components of the eukaryotic ubiquitin-proteasome system and are involved in the genesis of several human diseases. In this study, I analyze the patterns of diversification of HECT E3s since animals emerged in order to provide the right framework to understand the functional data available for proteins of this family. Results. I show that the current classification of HECT E3s into three groups (NEDD4-like E3s, HERCs and single-HECT E3s) is fundamentally incorrect. First, the existence of a "Single-HECT E3s" group is not supported by phylogenetic analyses. Second, the HERC proteins must be divided into two subfamilies (Large HERCs, Small HERCs) that are evolutionarily very distant, their structural similarity being due to convergence and not to a common origin. Sequence and structural analyses show that animal HECT E3s can be naturally classified into 16 subfamilies. Almost all of them appeared either before animals originated or in early animal evolution. More recently, multiple gene losses have occurred independently in some lineages (nematodes, insects, urochordates), the same groups that have also lost genes of another type of E3s (RBR family). Interestingly, the emergence of some animal HECT E3s precedes the origin of key cellular systems that they regulate (TGF- and EGF signal transduction pathways; p53 family of transcription factors) and it can be deduced that distantly related HECT proteins have been independently co-opted to perform similar roles. This may contribute to explain why distantly related HECT E3s are involved in the genesis of multiple types of cancer. Conclusions. The complex evolutionary history of HECT ubiquitin ligases in animals has been deciphered. The most appropriate model animals to study them and new theoretical and experimental lines of research are suggested by these results. © 2010 Marín; licensee BioMed Central Ltd.


Marin I.,Institute Biomedicina Of Valencia
BMC Evolutionary Biology | Year: 2014

Background: Ubiquilins are proteins that function as ubiquitin receptors in eukaryotes. Mutations in two ubiquilin-encoding genes have been linked to the genesis of neurodegenerative diseases. However, ubiquilin functions are still poorly understood. Results: In this study, evolutionary and functional data are combined to determine the origin and diversification of the ubiquilin gene family and to characterize novel potential roles of ubiquilins in mammalian species, including humans. The analysis of more than six hundred sequences allowed characterizing ubiquilin diversity in all the main eukaryotic groups. Many organisms (e. g. fungi, many animals) have single ubiquilin genes, but duplications in animal, plant, alveolate and excavate species are described. Seven different ubiquilins have been detected in vertebrates. Two of them, here called UBQLN5 and UBQLN6, had not been hitherto described. Significantly, marsupial and eutherian mammals have the most complex ubiquilin gene families, composed of up to 6 genes. This exceptional mammalian-specific expansion is the result of the recent emergence of four new genes, three of them (UBQLN3, UBQLN5 and UBQLNL) with precise testis-specific expression patterns that indicate roles in the postmeiotic stages of spermatogenesis. A gene with related features has independently arisen in species of the Drosophila genus. Positive selection acting on some mammalian ubiquilins has been detected. Conclusions: The ubiquilin gene family is highly conserved in eukaryotes. The infrequent lineage-specific amplifications observed may be linked to the emergence of novel functions in particular tissues. © 2014Marín; licensee BioMed Central Ltd.


Gallego del Sol F.,Institute Biomedicina Of Valencia | Marina A.,Institute Biomedicina Of Valencia
PLoS Biology | Year: 2013

Two-component systems, composed of a sensor histidine kinase and an effector response regulator (RR), are the main signal transduction devices in bacteria. In Bacillus, the Rap protein family modulates complex signaling processes mediated by two-component systems, such as competence, sporulation, or biofilm formation, by inhibiting the RR components involved in these pathways. Despite the high degree of sequence homology, Rap proteins exert their activity by two completely different mechanisms of action: inducing RR dephosphorylation or blocking RR binding to its target promoter. However the regulatory mechanism involving Rap proteins is even more complex since Rap activity is antagonized by specific signaling peptides (Phr) through a mechanism that remains unknown at the molecular level. Using X-ray analyses, we determined the structure of RapF, the anti-activator of competence RR ComA, alone and in complex with its regulatory peptide PhrF. The structural and functional data presented herein reveal that peptide PhrF blocks the RapF-ComA interaction through an allosteric mechanism. PhrF accommodates in the C-terminal tetratricopeptide repeat domain of RapF by inducing its constriction, a conformational change propagated by a pronounced rotation to the N-terminal ComA-binding domain. This movement partially disrupts the ComA binding site by triggering the ComA disassociation, whose interaction with RapF is also sterically impaired in the PhrF-induced conformation of RapF. Sequence analyses of the Rap proteins, guided by the RapF-PhrF structure, unveil the molecular basis of Phr recognition and discrimination, allowing us to relax the Phr specificity of RapF by a single residue change. © 2013 Marina, Gallego del Sol.


Calvete J.J.,Institute Biomedicina Of Valencia
Expert Review of Proteomics | Year: 2014

Venom research has been continuously enhanced by technological advances. High-throughput technologies are changing the classical paradigm of hypothesis-driven research to technology-driven approaches. However, the thesis advocated in this paper is that full proteome coverage at locus-specific resolution requires integrating the best of both worlds into a protocol that includes decomplexation of the venom proteome prior to liquid chromatography-tandem mass spectrometry matching against a species-specific transcriptome. This approach offers the possibility of proof-checking the species-specific contig database using proteomics data. Immunoaffinity chromatography constitutes the basis of an antivenomics workflow designed to quantify the extent of cross-reactivity of antivenoms against homologous and heterologous venom toxins. In the author's view, snake venomics and antivenomics form part of a biology-driven conceptual framework to unveil the genesis and natural history of venoms, and their within-and between-species toxicological and immunological divergences and similarities. Understanding evolutionary trends across venoms represents the Rosetta Stone for generating broad-ranging polyspecific antivenoms. © 2014 Informa UK, Ltd.


Garcia-Haro L.,Institute Biomedicina Of Valencia
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology | Year: 2010

Mammalian AMP-activated protein kinase (AMPK) is a serine/threonine protein kinase that acts as a sensor of cellular energy status. It is activated by phosphorylation of the catalytic subunit on Thr172. The main objective of this study was the identification of a phosphatase involved in the regulation of AMPK activity. Mouse MIN6 β cells were used to study the glucose-induced regulation of the phosphorylation of AMPK. Small interfering RNA (siRNA) technology was used to deplete putative phosphatase candidate genes that could affect AMPK regulation. The effect of the siRNAs used in the study was compared with the effect observed using a negative control siRNA. A protein phosphatase complex composed of the catalytic subunit of protein phosphatase-1 (PP1) and the regulatory subunit R6 participates in the glucose-induced dephosphorylation of AMPK. R6 interacts physically with the β-subunit of the AMPK complex and recruits PP1 to dephosphorylate the catalytic α-subunit on Thr172. siRNA depletion of R6 decreases glucose-induced insulin secretion due to the presence of a constitutively active AMPK complex. The characterization of the PP1-R6 complex identifies this holoenzyme as a possible target for therapeutic intervention with the aim of regulating the activity of AMPK in pancreatic β cells.


Marin I.,Institute Biomedicina Of Valencia
PLoS ONE | Year: 2010

Background: RBR ubiquitin ligases are components of the ubiquitin-proteasome system present in all eukaryotes. They are characterized by having the RBR (RING - IBR - RING) supradomain. In this study, the patterns of emergence of RBR genes in plants are described. Methodology/Principal Findings: Phylogenetic and structural data confirm that just four RBR subfamilies (Ariadne, ARA54, Plant I/Helicase and Plant II) exist in viridiplantae. All of them originated before the split that separated green algae from the rest of plants. Multiple genes of two of these subfamilies (Ariadne and Plant II) appeared in early plant evolution. It is deduced that the common ancestor of all plants contained at least five RBR genes and the available data suggest that this number has been increasing slowly along streptophyta evolution, although losses, especially of Helicase RBR genes, have also occurred in several lineages. Some higher plants (e. g. Arabidopsis thaliana, Oryza sativa) contain a very large number of RBR genes and many of them were recently generated by tandem duplications. Microarray data indicate that most of these new genes have low-level and sometimes specific expression patterns. On the contrary, and as occurs in animals, a small set of older genes are broadly expressed at higher levels. Conclusions/Significance: The available data suggests that the dynamics of appearance and conservation of RBR genes is quite different in plants from what has been described in animals. In animals, an abrupt emergence of many structurally diverse RBR subfamilies in early animal history, followed by losses of multiple genes in particular lineages, occurred. These patterns are not observed in plants. It is also shown that while both plants and animals contain a small, similar set of essential RBR genes, the rest evolves differently. The functional implications of these results are discussed. © 2010 Ignacio Marín.

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