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- 3D complex: a structural classification of protein complexesPublication . Levy, E.D.; Pereira-Leal, J.B.; Chothia, C.; Teichmann, S.A.Most of the proteins in a cell assemble into complexes to carry out their function. It is therefore crucial to understand the physicochemical properties as well as the evolution of interactions between proteins. The Protein Data Bank represents an important source of information for such studies, because more than half of the structures are homo- or heteromeric protein complexes. Here we propose the first hierarchical classification of whole protein complexes of known 3-D structure, based on representing their fundamental structural features as a graph. This classification provides the first overview of all the complexes in the Protein Data Bank and allows nonredundant sets to be derived at different levels of detail. This reveals that between one-half and two-thirds of known structures are multimeric, depending on the level of redundancy accepted. We also analyse the structures in terms of the topological arrangement of their subunits and find that they form a small number of arrangements compared with all theoretically possible ones. This is because most complexes contain four subunits or less, and the large majority are homomeric. In addition, there is a strong tendency for symmetry in complexes, even for heteromeric complexes. Finally, through comparison of Biological Units in the Protein Data Bank with the Protein Quaternary Structure database, we identified many possible errors in quaternary structure assignments. Our classification, available as a database and Web server at http://www.3Dcomplex.org, will be a starting point for future work aimed at understanding the structure and evolution of protein complexes
- Actin stress fiber organization promotes cell stiffening and proliferation of pre-invasive breast cancer cellsPublication . Tavares, Sandra; Vieira, André Filipe; Taubenberger, Anna Verena; Araújo, Margarida; Martins, Nuno Pimpao; Brás-Pereira, Catarina; Polónia, António; Herbig, Maik; Barreto, Clara; Otto, Oliver; Cardoso, Joana; Pereira-Leal, José B.; Guck, Jochen; Paredes, Joana; Janody, FlorenceStudies of the role of actin in tumour progression have highlighted its key contribution in cell softening associated with cell invasion. Here, using a human breast cell line with conditional Src induction, we demonstrate that cells undergo a stiffening state prior to acquiring malignant features. This state is characterized by the transient accumulation of stress fibres and upregulation of Ena/VASP-like (EVL). EVL, in turn, organizes stress fibres leading to transient cell stiffening, ERK-dependent cell proliferation, as well as enhancement of Src activation and progression towards a fully transformed state. Accordingly, EVL accumulates predominantly in premalignant breast lesions and is required for Src-induced epithelial overgrowth in Drosophila. While cell softening allows for cancer cell invasion, our work reveals that stress fibre-mediated cell stiffening could drive tumour growth during premalignant stages. A careful consideration of the mechanical properties of tumour cells could therefore offer new avenues of exploration when designing cancer-targeting therapies.
- Aurora at the pole and equator: overlapping functions of Aurora kinases in the mitotic spindlePublication . Hochegger, H.; Hegarat, N.; Pereira-Leal, J. B.The correct assembly and timely disassembly of the mitotic spindle is crucial for the propagation of the genome during cell division. Aurora kinases play a central role in orchestrating bipolar spindle establishment, chromosome alignment and segregation. In most eukaryotes, ranging from amoebas to humans, Aurora activity appears to be required both at the spindle pole and the kinetochore, and these activities are often split between two different Aurora paralogues, termed Aurora A and B. Polar and equatorial functions of Aurora kinases have generally been considered separately, with Aurora A being mostly involved in centrosome dynamics, whereas Aurora B coordinates kinetochore attachment and cytokinesis. However, double inactivation of both Aurora A and B results in a dramatic synergy that abolishes chromosome segregation. This suggests that these two activities jointly coordinate mitotic progression. Accordingly, recent evidence suggests that Aurora A and B work together in both spindle assembly in metaphase and disassembly in anaphase. Here, we provide an outlook on these shared functions of the Auroras, discuss the evolution of this family of mitotic kinases and speculate why Aurora kinase activity may be required at both ends of the spindle microtubules.
- Collective electrical oscillations of a diatom population induced by dark stressPublication . Rocha, Paulo R. F.; Silva, Alexandra D.; Godinho, Lia; Dane, Willem; Estrela, Pedro; Vandamme, Lode K. J.; Pereira-Leal, Jose B.; de Leeuw, Dago M.; Leite, Ricardo B.Diatoms are photosynthetic microalgae, a group with a major environmental role on the planet due to the biogeochemical cycling of silica and global fixation of carbon. However, they can evolve into harmful blooms through a resourceful communication mechanism, not yet fully understood. Here, we demonstrate that a population of diatoms under darkness show quasi-periodic electrical oscillations, or intercellular waves. The origin is paracrine signaling, which is a feedback, or survival, mechanism that counteracts changes in the physicochemical environment. The intracellular messenger is related to Ca2+ions since spatiotemporal changes in their concentration match the characteristics of the intercellular waves. Our conclusion is supported by using a Ca2+channel inhibitor. The transport of Ca2+ions through the membrane to the extracellular medium is blocked and the intercellular waves disappear. The translation of microalgae cooperative signaling paves the way for early detection and prevention of harmful blooms and an extensive range of stress-induced alterations in the aquatic ecosystem.
- A comprehensive assessment of the transcriptome of cork oak (Quercus suber) through EST sequencingPublication . Pereira-Leal, José B; Abreu, Isabel A; Alabaça, Cláudia S; Almeida, Maria; Almeida, Paulo; Almeida, Tânia; Amorim, Maria; Araújo, Susana; Azevedo, Herlânder; Badia, Aleix; Batista, Dora; Bohn, Andreas; Capote, Tiago; Carrasquinho, Isabel; Chaves, Inês; Coelho, Ana; Costa, Maria; Costa, Rita; Cravador, Alfredo; Egas, Conceição; Faro, Carlos; Fortes, Ana M; Fortunato, Ana S; Gaspar, Maria; Gonçalves, Sónia; Graça, José; Horta, Marília; Inácio, Vera; Leitão, José M; Lino-Neto, Teresa; Marum, Liliana; Matos, José; Mendonça, Diogo; Miguel, Andreia; Miguel, Célia M; Morais-Cecílio, Leonor; Neves, Isabel; Nóbrega, Filomena; Oliveira, Maria; Oliveira, Rute; Pais, Maria; Paiva, Jorge A; Paulo, Octávio S; Pinheiro, Miguel; Raimundo, João AP; Ramalho, José C; Ribeiro, Ana I; Ribeiro, Teresa; Rocheta, Margarida; Rodrigues, Ana; Rodrigues, José C; Saibo, Nelson JM; Santo, Tatiana E; Santos, Ana; Sá-Pereira, Paula; Sebastiana, Mónica; Simões, Fernanda; Sobral, Rómulo S; Tavares, Rui; Teixeira, Rita; Varela, Carolina; Veloso, Maria; Ricardo, Cândido PPCork oak (Quercus suber) is one of the rare trees with the ability to produce cork, a material widely used to make wine bottle stoppers, flooring and insulation materials, among many other uses. The molecular mechanisms of cork formation are still poorly understood, in great part due to the difficulty in studying a species with a long life-cycle and for which there is scarce molecular/genomic information. Cork oak forests are of great ecological importance and represent a major economic and social resource in Southern Europe and Northern Africa. However, global warming is threatening the cork oak forests by imposing thermal, hydric and many types of novel biotic stresses. Despite the economic and social value of the Q. suber species, few genomic resources have been developed, useful for biotechnological applications and improved forest management.
- CYR61 and TAZ Upregulation and Focal Epithelial to Mesenchymal Transition May Be Early Predictors of Barrett’s Esophagus Malignant ProgressionPublication . Cardoso, Joana; Mesquita, Marta; Dias Pereira, António; Bettencourt-Dias, Mónica; Chaves, Paula; Pereira-Leal, José B.Barrett's esophagus is the major risk factor for esophageal adenocarcinoma. It has a low but non-neglectable risk, high surveillance costs and no reliable risk stratification markers. We sought to identify early biomarkers, predictive of Barrett's malignant progression, using a meta-analysis approach on gene expression data. This in silico strategy was followed by experimental validation in a cohort of patients with extended follow up from the Instituto Português de Oncologia de Lisboa de Francisco Gentil EPE (Portugal). Bioinformatics and systems biology approaches singled out two candidate predictive markers for Barrett's progression, CYR61 and TAZ. Although previously implicated in other malignancies and in epithelial-to-mesenchymal transition phenotypes, our experimental validation shows for the first time that CYR61 and TAZ have the potential to be predictive biomarkers for cancer progression. Experimental validation by reverse transcriptase quantitative PCR and immunohistochemistry confirmed the up-regulation of both genes in Barrett's samples associated with high-grade dysplasia/adenocarcinoma. In our cohort CYR61 and TAZ up-regulation ranged from one to ten years prior to progression to adenocarcinoma in Barrett's esophagus index samples. Finally, we found that CYR61 and TAZ over-expression is correlated with early focal signs of epithelial to mesenchymal transition. Our results highlight both CYR61 and TAZ genes as potential predictive biomarkers for stratification of the risk for development of adenocarcinoma and suggest a potential mechanistic route for Barrett's esophagus neoplastic progression.
- Evolutionary cell biology: two origins, one objectivePublication . Lynch, Michael; Field, Mark C; Goodson, Holly V; Malik, Harmit S; Pereira-Leal, José B; Roos, David S; Turkewitz, Aaron P; Sazer, ShelleyAll aspects of biological diversification ultimately trace to evolutionary modifications at the cellular level. This central role of cells frames the basic questions as to how cells work and how cells come to be the way they are. Although these two lines of inquiry lie respectively within the traditional provenance of cell biology and evolutionary biology, a comprehensive synthesis of evolutionary and cell-biological thinking is lacking. We define evolutionary cell biology as the fusion of these two eponymous fields with the theoretical and quantitative branches of biochemistry, biophysics, and population genetics. The key goals are to develop a mechanistic understanding of general evolutionary processes, while specifically infusing cell biology with an evolutionary perspective. The full development of this interdisciplinary field has the potential to solve numerous problems in diverse areas of biology, including the degree to which selection, effectively neutral processes, historical contingencies, and/or constraints at the chemical and biophysical levels dictate patterns of variation for intracellular features. These problems can now be examined at both the within- and among-species levels, with single-cell methodologies even allowing quantification of variation within genotypes. Some results from this emerging field have already had a substantial impact on cell biology, and future findings will significantly influence applications in agriculture, medicine, environmental science, and synthetic biology.
- Evolutionary Patterns in Coiled-CoilsPublication . Surkont, J.; Pereira-Leal, J. B.Models of protein evolution are used to describe evolutionary processes, for phylogenetic analyses and homology detection. Widely used general models of protein evolution are biased toward globular domains and lack resolution to describe evolutionary processes for other protein types. As three-dimensional structure is a major constraint to protein evolution, specific models have been proposed for other types of proteins. Here, we consider evolutionary patterns in coiled-coil forming proteins. Coiled-coils are widespread structural domains, formed by a repeated motif of seven amino acids (heptad repeat). Coiled-coil forming proteins are frequently rods and spacers, structuring both the intracellular and the extracellular spaces that often form protein interaction interfaces. We tested the hypothesis that due to their specific structure the associated evolutionary constraints differ from those of globular proteins. We showed that substitution patterns in coiled-coil regions are different than those observed in globular regions, beyond the simple heptad repeat. Based on these substitution patterns we developed a coiled-coil specific (CC) model that in the context of phylogenetic reconstruction outperforms general models in tree likelihood, often leading to different topologies. For multidomain proteins containing both a coiled-coil region and a globular domain, we showed that a combination of the CC model and a general one gives higher likelihoods than a single model. Finally, we showed that the model can be used for homology detection to increase search sensitivity for coiled-coil proteins. The CC model, software, and other supplementary materials are available at http://www.evocell.org/cgl/resources (last accessed January 29, 2015).
- Genetic Competence Drives Genome Diversity in Bacillus subtilisPublication . Brito, Patrícia H; Chevreux, Bastien; Serra, Cláudia R; Schyns, Ghislain; Henriques, Adriano O; Pereira-Leal, José BProkaryote genomes are the result of a dynamic flux of genes, with increases achieved via horizontal gene transfer and reductions occurring through gene loss. The ecological and selective forces that drive this genomic flexibility vary across species. Bacillus subtilis is a naturally competent bacterium that occupies various environments, including plant-associated, soil, and marine niches, and the gut of both invertebrates and vertebrates. Here, we quantify the genomic diversity of B. subtilis and infer the genome dynamics that explain the high genetic and phenotypic diversity observed. Phylogenomic and comparative genomic analyses of 42 B. subtilis genomes uncover a remarkable genome diversity that translates into a core genome of 1,659 genes and an asymptotic pangenome growth rate of 57 new genes per new genome added. This diversity is due to a large proportion of low-frequency genes that are acquired from closely related species. We find no gene-loss bias among wild isolates, which explains why the cloud genome, 43% of the species pangenome, represents only a small proportion of each genome. We show that B. subtilis can acquire xenologous copies of core genes that propagate laterally among strains within a niche. While not excluding the contributions of other mechanisms, our results strongly suggest a process of gene acquisition that is largely driven by competence, where the long-term maintenance of acquired genes depends on local and global fitness effects. This competence-driven genomic diversity provides B. subtilis with its generalist character, enabling it to occupy a wide range of ecological niches and cycle through them.
- Genome of a Gut Strain of Bacillus subtilisPublication . Schyns, G.; Serra, C. R.; Lapointe, T.; Pereira-Leal, J. B.; Potot, S.; Fickers, P.; Perkins, J. B.; Wyss, M.; Henriques, A. O.Bacillus subtilis is a Gram-positive, rod-shaped, spore-forming bacterium. We present the genome sequence of an undomesticated strain, BSP1, isolated from poultry. The sequence of the BSP1 genome supports the view that B. subtilis has a biphasic lifestyle, cycling between the soil and the animal gastrointestinal tract, and it provides molecular-level insight into the adaptation of B. subtilis to life under laboratory conditions.
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