3DBionotes COVID-19 edition.

Summary: The web platform 3DBionotes-WS integrates multiple web services and an interactive web viewer to provide a unified environment in which biological annotations can be analyzed in their structural context. Since the COVID-19 outbreak, new structural data from many viral proteins have been provided at a very fast pace. This effort includes many cryogenic electron microscopy (cryo-EM) studies, together with more traditional ones (X-rays, NMR), using several modeling approaches and complemented with structural predictions.

3DBIONOTES v3.0: crossing molecular and structural biology data with genomic variations.

Motivation: Many diseases are associated to single nucleotide polymorphisms that affect critical regions of proteins as binding sites or post translational modifications. Therefore, analysing genomic variants with structural and molecular biology data is a powerful framework in order to elucidate the potential causes of such diseases.

Results: A new version of our web framework 3DBIONOTES is presented.

Tuning Optoelectronic and Chiroptic Properties of Peptide-Based Materials by Controlling the Pathway Complexity.

Supramolecular chemistry has evolved from the traditional focus on thermodynamic on-pathways to the complex study of kinetic off-pathways, which are strongly dependent on environmental conditions. Moreover, the control over pathway complexity allows nanostructures to be obtained that are inaccessible through spontaneous thermodynamic processes. Herein, we present a family of peptide-based π-extended tetrathiafulvalene (exTTF) molecules that show two self-assembly pathways leading to two distinct J-aggregates, namely metastable (M) and thermodynamic (T), with different spectroscopic, chiroptical, and electrochemical behavior.

Involvement of the cellular phosphatase DUSP1 in vaccinia virus infection.

Poxviruses encode a large variety of proteins that mimic, block or enhance host cell signaling pathways on their own benefit. It has been reported that mitogen-activated protein kinases (MAPKs) are specifically upregulated during vaccinia virus (VACV) infection. Here, we have evaluated the role of the MAPK negative regulator dual specificity phosphatase 1 (DUSP1) in the infection of VACV.

Molecular and cellular dynamics at the early stages of antigen encounter: the B-cell immunological synapse.

The recent development and application of sophisticated technology in the study of the initial stages of the B-cell immune response has lead to a tremendous revolution in the field. The use of real-time confocal microscopy, total interference reflection fluorescence (TIRF) microscopy and in vitro models has revealed the molecular details of the antigen recognition process by B cells. Moreover, experimental models that allow tracking of antigen in vivo in concert with multiphoton microscopy have provided critical information as to the how, where, and when naïve B cells encounter antigen in vivo.

Imaging techniques: new insights into chemokine/chemokine receptor biology at the immune system.

Our current knowledge of molecular and cellular responses in vivo is based mainly on event reconstruction from time-freeze observations. Conventional biochemical and genetic methods consider the cell as an individual entity and ligand/receptor pairs as isolated systems. In addition, the data refer to the average behavior of a pool of cells and/or receptors removed from their real-life context.

Streptococcus pyogenes pSM19035 requires dynamic assembly of ATP-bound ParA and ParB on parS DNA during plasmid segregation.

The accurate partitioning of Firmicute plasmid pSM19035 at cell division depends on ATP binding and hydrolysis by homodimeric ATPase delta(2) (ParA) and binding of omega(2) (ParB) to its cognate parS DNA. The 1.83 A resolution crystal structure of delta(2) in a complex with non-hydrolyzable ATPgammaS reveals a unique ParA dimer assembly that permits nucleotide exchange without requiring dissociation into monomers.

Downstream regulatory element antagonist modulator regulates Ca2+ homeostasis and viability in cerebellar neurons.

The Na+/Ca2+ exchangers NCX1, NCX2, and NCX3 are vital for the control of cellular Ca2+ homeostasis. Here, we show that a doublet of downstream regulatory element sites in the promoter of the NCX3 gene mediates transcriptional repression of NCX3 by the Ca2+-modulated transcriptional repressor downstream regulatory element antagonist modulator (DREAM). Overexpression of a DREAM EF-hand mutant insensitive to Ca2+ (EFmDREAM) in hippocampus and cerebellum of transgenic mice significantly reduced NCX3 mRNA and protein levels without modifying NCX1 and NCX2 expression.

Mammalian telomeres and telomerase: why they matter for cancer and aging.

Chromosome ends, or telomeres, are formed by a special chromatin structure that protects them from recombination and degradation, thus preventing end-to-end chromosome fusions and other chromosomal aberrations. The functionality of telomeres, and that of the cellular activity that synthesizes them, telomerase, has been shown to impact on both cancer and aging, as well as on the organismal sensitivity to ionizing radiation. This review focuses on the analysis of different mouse models for proteins that are important for telomere function, which have highlighted the importance of telomeres and telomerase for cancer and aging.

Evolving views of telomerase and cancer.

The maintenance of telomeres, nucleoprotein structures that constitute the ends of eukaryotic chromosomes, regulates many crucial cellular functions and might, in multicellular organisms, participate in the control of complex phenotypes such as aging and cancer. Stabilization of telomere length is strongly associated with cellular immortalization, and constitutive telomerase activation occurs in most human cancers. Such observations form the basis for the prevailing model that postulates that alterations in telomere biology both suppress and facilitate malignant transformation by regulating genomic stability and cell life span.

Engineering cancer resistance in mice.

Research on cancer has benefited enormously from the genetic manipulation of mice. Until recently, most of the emphasis has been put on tailoring genetic alterations to accelerate tumorigenesis or to recapitulate particular aspects of the tumorigenic process. The goal of engineering mice with an increased resistance to cancer is a novel aspect that is of importance to understand cancer susceptibility and to validate therapeutic and chemopreventive strategies.

Telomeres in cancer and aging: lessons from the mouse.

The analysis of mice deficient in telomerase activity has allowed to directly test the relevance of telomeres and telomerase in tumor development and aging in the context of a mammalian organism. More recently, mice with impaired telomere capping due to abrogation of telomere-binding proteins have been also characterized. Here, I will discuss these studies, as well as their implications for putative therapies based of telomerase inhibition of telomerase re-introduction for cancer or age-related diseases, respectively.

Telomeres and cancer: a tale with many endings.

Telomerase activity is necessary to maintain the integrity of telomeres, which in turn prevent chromosome ends from being processed and signaled as damaged DNA. That cancer cells rely on telomerase to maintain functional telomeres and to divide indefinitely has highlighted the potential for developing novel therapeutic approaches that target telomerase.

Mouse models to study the role of telomeres in cancer, aging and DNA repair.

The chromosome ends have protective structures that distinguish them from broken chromosomes, known as telomeres. The function of telomeres, and that of the cellular activity that synthesises them, telomerase, are proposed to be biological determinants in the processes of cancer and aging. In this review, we will focus on mammalian telomeres and, in particular, on the analysis of different mouse models for proteins that are important for telomere function, such as telomerase and various telomere-binding proteins.

Functional interaction between DNA-PKcs and telomerase in telomere length maintenance.

DNA-PKcs is the catalytic subunit of the DNA-dependent protein kinase (DNA-PK) complex that functions in the non-homologous end-joining of double-strand breaks, and it has been shown previously to have a role in telomere capping. In particular, DNA-PKcs deficiency leads to chromosome fusions involving telomeres produced by leading-strand synthesis. Here, by generating mice doubly deficient in DNA-PKcs and telomerase (Terc(-/-)/DNA-PKcs(-/-)), we demonstrate that DNA-PKcs also has a fundamental role in telomere length maintenance.

An essential role for functional telomeres in mouse germ cells during fertilization and early development.

Late generations of telomerase-null (TR(-/-)) mice exhibit progressive defects in highly proliferative tissues and organs and decreased fertility, ultimately leading to sterility. To determine effects of telomerase deficiency on germ cells, we investigated the cleavage and preimplantation development of embryos derived from both in vivo and in vitro fertilization of TR(-/-) or wild-type (TR(+/+)) sperm with either TR(-/-) or TR(+/+) oocytes. Consistently, fertilization of TR(-/-) oocytes with either TR(+/+) or TR(-/-) sperm, and TR(-/-) sperm with TR(+/+) oocytes, resulted in aberrant cleavage and development, in contrast to the normal cleavage and development of TR(+/+) oocytes fertilized by TR(+/+) sperm.

Telomerase beyond telomeres.

The role of telomerase in actively proliferating cells is assumed to be restricted to maintaining of telomeres above a minimum-length threshold, thereby preventing telomere exhaustion and chromosomal instability. However, forced telomerase expression in cells and mice with normal-length telomeres has shown that telomerase promotes growth and survival in a manner that is uncoupled from net telomere lengthening. These findings imply that telomerase might have a fundamental role in tumour growth and survival, even at stages when telomeres are sufficiently long.

Mammalian meiotic telomeres: composition and ultrastructure in telomerase-deficient mice.

During early meiotic prophase chromosome ends become attached to the nuclear envelope, a process that is essential for faithful homologue pairing and segregation. The factors involved in this attachment are largely unknown. Here we investigated the possible involvement of telomere chromatin by using late generation (G5 and G6) Terc-/- mice.

Activation of ARF by oncogenic stress in mouse fibroblasts is independent of E2F1 and E2F2.

The ARF tumour suppressor protein (p14(ARF) in human and p19(ARF) in mouse) is a major mediator of the activation of p53 in response to oncogenic stress. Little is known about the signalling pathways connecting oncogenic stimuli to the activation of ARF. Regulation of ARF occurs primarily at the transcriptional level and several modulators of ARF transcription have been identified.

Decreased B16F10 melanoma growth and impaired vascularization in telomerase-deficient mice with critically short telomeres.

Endothelial cell function and angiogenesis are modulated by aging. However, the underlying molecular mechanisms are largely unknown. Here we show that in telomerase-deficient mice Terc(-/-), short telomeres result in a sharp decrease in angiogenesis in both Matrigel implants and murine melanoma grafts.