Search and sequence analysis tools services from EMBL-EBI in 2022

Madeira, Fábio; Pearce, Matt; Tivey, Adrian; Basutkar, Prasad; Lee, Joon; Edbali, Ossama; Madhusoodanan, Nandana; Kolesnikov, Anton; López, Rodrigo

doi:10.1093/nar/gkac240

Cited by 1,548 publications

(1,178 citation statements)

References 31 publications

(29 reference statements)

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“…Homologs of the major capsid proteins in BASEL phages were identified by BLASTp 48 searches against each phage genome. Homologs of Gp57 (Gp8 Bas4 , Gp8 Bas5 , Gp8 Bas8 ) were aligned by MUSCLE 49 and colored by percent identity (Fig. S5a).…”

Section: Methodsmentioning

confidence: 99%

Direct activation of an innate immune system in bacteria by a viral capsid protein

Zhang

Tamman

Wallant

et al. 2022

Preprint

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Bacteria have evolved sophisticated and diverse immunity mechanisms to protect themselves against a nearly constant onslaught of bacteriophages. Similar to how eukaryotic innate immune systems sense foreign invaders through pathogen-associated molecular patterns (PAMPs), many bacterial immune systems that respond to bacteriophage infection require a phage-specific trigger to be activated. However, the identities of such triggers and the mechanistic basis of sensing remain almost completely unknown. Here, we discover and investigate the anti-phage function of a fused toxin-antitoxin (TA) system called CapRelSJ46 that protects E. coli against diverse phages. Through genetic, biochemical, and structural analysis, we demonstrate that the C-terminal domain of CapRelSJ46 regulates the toxic N-terminal region, serving as both an antitoxin element and a phage-infection sensor. Following infection by certain phages, the newly synthesized major capsid protein binds directly to the C-terminal domain of CapRelSJ46 to relieve autoinhibition, enabling the toxin domain to then pyrophosphorylate tRNAs, which blocks translation to restrict viral infection. Collectively, our results reveal the molecular mechanism by which a bacterial immune system directly senses a conserved, essential component of phages, suggesting a PAMP-like sensing model for TA-mediated innate immunity in bacteria. We provide evidence that CapRels and their phage-encoded triggers are engaged in a Red Queen conflict, revealing a new front in the intense coevolutionary battle being waged by phage and bacteria. With capsid proteins of some eukaryotic viruses known to stimulate innate immune signaling in mammalian hosts, our results now reveal an ancient, deeply conserved facet of immunity.

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Section: Methodsmentioning

confidence: 99%

Direct activation of an innate immune system in bacteria by a viral capsid protein

Zhang

Tamman

Wallant

et al. 2022

Preprint

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“…A sequence alignment of deduced amino acids was performed via ClustalO with the default parameters [ 37 ]. Phylogenetic analyses were conducted in MEGA X [ 38 ].…”

Section: Methodsmentioning

confidence: 99%

An Aux/IAA Family Member, RhIAA14, Involved in Ethylene-Inhibited Petal Expansion in Rose (Rosa hybrida)

Jia

Chen

Gong

et al. 2022

Genes

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Flower size, a primary agronomic trait in breeding of ornamental plants, is largely determined by petal expansion. Generally, ethylene acts as an inhibitor of petal expansion, but its effect is restricted by unknown developmental cues. In this study, we found that the critical node of ethylene-inhibited petal expansion is between stages 1 and 2 of rose flower opening. To uncover the underlying regulatory mechanism, we carried out a comparative RNA-seq analysis. Differentially expressed genes (DEGs) involved in auxin-signaling pathways were enriched. Therefore, we identified an auxin/indole-3-acetic acid (Aux/IAA) family gene, RhIAA14, whose expression was development-specifically repressed by ethylene. The silencing of RhIAA14 reduced cell expansion, resulting in diminished petal expansion and flower size. In addition, the expressions of cell-expansion-related genes, including RhXTH6, RhCesA2, RhPIP2;1, and RhEXPA8, were significantly downregulated following RhIAA14 silencing. Our results reveal an Aux/IAA that serves as a key player in orchestrating petal expansion and ultimately contributes to flower size, which provides new insights into ethylene-modulated flower opening and the function of the Aux/IAA transcription regulator.

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“…We have obtained a protein multiple sequence alignment between different AMBRA1 orthologs using Clustal Omega [50], using the protein sequences corresponding to the main protein isoform of AMBRA1 of human, chimpanzee, mouse, rat, bovine, Xenopus and zebrafish (ambra1a for the latter).…”

Section: Methodsmentioning

confidence: 99%

The Cancermuts software package for the prioritization of missense cancer variants: a case study of AMBRA1 in melanoma

Tiberti

Leo

Vistesen

et al. 2022

Preprint

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Cancer genomics and cancer mutation databases have made a wealth of information about missense mutations found in cancer patient samples. Contextualizing by means of annotation and predicting the effect of amino acid change help identify which ones are more likely to have a pathogenic impact. Those can be validated by means of experimental approaches that assess the impact of protein mutations on the cellular functions or their tumorigenic potential. Here, we propose the integrative bioinformatic approach Cancermuts, implemented as a Python package. Cancermuts is able to gather known missense cancer mutations from databases such as cBioPortal and COSMIC, and annotate them with the pathogenicity score REVEL as well as information on their source. It is also able to add annotations about the protein context these mutations are found in, such as post-translational modification sites, structured/ustructured regions, presence of short linear motifs and more. We applied Cancermuts to the intrinsically disordered protein AMBRA1, a key regulator of many cellular processes tightly (de)regulated in cancer. By these means, we classified mutations of AMBRA1 in melanoma, where AMBRA1 is highly mutated and displays a tumor-suppressive role. Next, based on REVEL score, position along the sequence and their local context, we applied cellular and molecular approaches to validate the predicted pathogenicity of a subset of mutations in an in vitro melanoma model. By doing so, we have identified two AMBRA1 mutations which show enhanced tumorigenic potential and are worth further investigation, highlighting the usefulness of the tool. Cancermuts can be used on any protein targets starting from minimal information, and it is available at https://www.github.com/ELELAB/cancermuts as free software.

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Search and sequence analysis tools services from EMBL-EBI in 2022

Cited by 1,548 publications

References 31 publications

Direct activation of an innate immune system in bacteria by a viral capsid protein

Direct activation of an innate immune system in bacteria by a viral capsid protein

An Aux/IAA Family Member, RhIAA14, Involved in Ethylene-Inhibited Petal Expansion in Rose (Rosa hybrida)

The Cancermuts software package for the prioritization of missense cancer variants: a case study of AMBRA1 in melanoma

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