Recognition of conserved amino acid motifs of common viruses and its role in autoimmunity.
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ABSTRACT:
SUBMITTER: Sospedra M
PROVIDER: S-EPMC1315278 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Coordinated variation among positions in amino acid sequence alignments can reveal genetic dependencies at noncontiguous positions, but methods to assess these interactions are incompletely developed. Previously, we found genome-wide networks of covarying residue positions in the hepatitis C virus genome (R. Aurora, M. J. Donlin, N. A. Cannon, and J. E. Tavis, J. Clin. Invest. 119:225-236, 2009). Here, we asked whether such networks are present in a diverse set of viruses and, if so, what they may imply about viral biology. Viral sequences were obtained for 16 viruses in 13 species from 9 families. The entire viral coding potential for each virus was aligned, all possible amino acid covariances were identified using the observed-minus-expected-squared algorithm at a false-discovery rate of ?1%, and networks of covariances were assessed using standard methods. Covariances that spanned the viral coding potential were common in all viruses. In all cases, the covariances formed a single network that contained essentially all of the covariances. The hepatitis C virus networks had hub-and-spoke topologies, but all other networks had random topologies with an unusually large number of highly connected nodes. These results indicate that genome-wide networks of genetic associations and the coordinated evolution they imply are very common in viral genomes, that the networks rarely have the hub-and-spoke topology that dominates other biological networks, and that network topologies can vary substantially even within a given viral group. Five examples with hepatitis B virus and poliovirus are presented to illustrate how covariance network analysis can lead to inferences about viral biology.
| S-EPMC3302335 | biostudies-literature
Project description:The micronemal protein 2 (MIC2) of Toxoplasma gondii shares sequence and structural similarities with a series of adhesive molecules of different apicomplexan parasites. These molecules accumulate, through a yet unknown mechanism, in secretory vesicles (micronemes), which together with tubular and membrane structures form the locomotion and invasion machinery of apicomplexan parasites. Our findings indicated that two conserved motifs placed within the cytoplasmic domain of MIC2 are both necessary and sufficient for targeting proteins to T. gondii micronemes. The first motif is based around the amino acid sequence SYHYY. Database analysis revealed that a similar sequence is present in the cytoplasmic tail of all transmembrane micronemal proteins identified so far in different apicomplexan species. The second signal consists of a stretch of acidic residues, EIEYE. The creation of an artificial tail containing only the two motifs SYHYY and EIEYE in a preserved spacing configuration is sufficient to target the surface protein SAG1 to the micronemes of T. gondii. These findings shed new light on the molecular mechanisms that control the formation of the microneme content and the functional relationship that links these organelles with the endoplasmic reticulum of the parasite.
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Project description:Superantigens are toxins produced by Staphylococcus aureus, called staphylococcal enterotoxins (abbreviated SEA to SEU). They can cross-link the T cell receptor (TCR) and major histocompatibility complex class II, triggering a massive T cell activation and hence disease. Due to high stability and toxicity, superantigens are potential agents of bioterrorism. Hence, antagonists may not only be useful in the treatment of disease but also serve as countermeasures to biological warfare. Of particular interest are inhibitors against SEA and SEB. SEA is the main cause of food poisoning, while SEB is a common toxin manufactured as a biological weapon. Here, we present the crystal structures of SEA in complex with TCR and SEE in complex with the same TCR, complemented with computational alanine-scanning mutagenesis of SEA, SEB, SEC3, SEE, and SEH. We have identified two common areas that contribute to the general TCR binding for these superantigens. This paves the way for design of single antagonists directed towards multiple toxins.
| S-EPMC4867771 | biostudies-literature
Project description:Throughout three domains of life, alanyl-tRNA synthetases (AlaRSs) recognize a G3:U70 base pair in the acceptor stem of tRNAAla as the major identity determinant of tRNAAla The crystal structure of the archaeon Archaeoglobus fulgidus AlaRS in complex with tRNAAla provided the basis for G3:U70 recognition with residues (Asp and Asn) that are conserved in the three domains [Naganuma M, et al. (2014) Nature 510:507-511]. The recognition mode is unprecedented, with specific accommodation of the dyad asymmetry of the G:U wobble pair and exclusion of the dyad symmetry of a Watson-Crick pair. With this conserved mode, specificity is based more on "fit" than on direct recognition of specific atomic groups. Here, we show that, in contrast to the archaeal complex, the Escherichia coli enzyme uses direct positive (energetically favorable) minor groove recognition of the unpaired 2-amino of G3 by Asp and repulsion of a competing base pair by Asn. Strikingly, mutations that disrupted positive recognition by the E. coli enzyme had little or no effect on G:U recognition by the human enzyme. Alternatively, Homo sapiens AlaRS selects G:U without positive recognition and uses Asp instead to repel a competitor. Thus, the widely conserved Asp-plus-Asn architecture of AlaRSs can select G:U in a straightforward (bacteria) or two different unconventional (eukarya/archaea) ways. The adoption of different modes for recognition of a widely conserved G:U pair in alanine tRNAs suggests an early and insistent role for G:U in the development of the genetic code.
| S-EPMC6055181 | biostudies-literature
Project description:BackgroundThe mouse vomeronasal organ (VNO) processes chemosensory information, including pheromone signals that influence reproductive behaviors. The sensory neurons of the VNO express two types of chemosensory receptors, V1R and V2R. There are ~165 V1R genes in the mouse genome that have been classified into ~12 divergent subfamilies. Each sensory neuron of the apical compartment of the VNO transcribes only one of the repertoire of V1R genes. A model for mutually exclusive V1R transcription in these cells has been proposed in which each V1R gene might compete stochastically for a single transcriptional complex. This model predicts that the large repertoire of divergent V1R genes in the mouse genome contains common regulatory elements. In this study, we have characterized V1R promoter regions by comparative genomics and by mapping transcription start sites.ResultsWe find that transcription is initiated from ~1 kb promoter regions that are well conserved within V1R subfamilies. While cross-subfamily homology is not evident by traditional methods, we developed a heuristic motif-searching tool, LogoAlign, and applied this tool to identify motifs shared within the promoters of all V1R genes. Our motif-searching tool exhibits rapid convergence to a relatively small number of non-redundant solutions (97% convergence). We also find that the best motifs contain significantly more information than those identified in controls, and that these motifs are more likely to be found in the immediate vicinity of transcription start sites than elsewhere in gene blocks. The best motifs occur near transcription start sites of ~90% of all V1R genes and across all of the divergent subfamilies. Therefore, these motifs are candidate binding sites for transcription factors involved in V1R co-regulation.ConclusionOur analyses show that V1R subfamilies have broad and well conserved promoter regions from which transcription is initiated. Results from a new motif-finding algorithm, LogoAlign, designed for this context and more generally for searching large, hierarchical datasets, suggest the existence of common information-rich regulatory motifs that are shared across otherwise divergent V1R subfamilies.
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Project description:The degradation of TNFM-NM-1 mRNA is critical for restricting TNFM-NM-1 synthesis and involves a constitutive decay element (CDE) in the 3M-bM-^@M-^Y untranslated region of the mRNA. We demonstrate that the active CDE is a stem-loop RNA motif that is recognized by the RNA-binding protein Roquin. Deep sequencing of Roquin-associated mRNAs identified CDE-containing mRNAs as the primary targets of Roquin on a transcriptome-wide scale. Expression profiles of LPS treated Raw264.7 cells (input), after Roquin IP or control IP were generated by deep sequencing, in three biological replicates, using Illumina HiSeq 2000.
2013-05-15 | E-GEOD-44775 | biostudies-arrayexpress
Project description:That amino acid properties are responsible for the way protein molecules evolve is natural and is also reasonably well supported both by the structure of the genetic code and, to a large extent, by the experimental measures of the amino acid similarity. Nevertheless, there remains a significant gap between observed similarity matrices and their reconstructions from amino acid properties. Therefore, we introduce a simple theoretical model of amino acid similarity matrices, which allows splitting the matrix into two parts - one that depends only on mutabilities of amino acids and another that depends on pairwise similarities between them. Then the new synthetic amino acid properties are derived from the pairwise similarities and used to reconstruct similarity matrices covering a wide range of information entropies. Our model allows us to explain up to 94% of the variability in the BLOSUM family of the amino acids similarity matrices in terms of amino acid properties. The new properties derived from amino acid similarity matrices correlate highly with properties known to be important for molecular evolution such as hydrophobicity, size, shape and charge of amino acids. This result closes the gap in our understanding of the influence of amino acids on evolution at the molecular level. The methods were applied to the single family of similarity matrices used often in general sequence homology searches, but it is general and can be used also for more specific matrices. The new synthetic properties can be used in analyzes of protein sequences in various biological applications.
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Project description:Accumulating evidence suggests that pathogenic TAR DNA-binding protein (TDP)-43 fragments contain a partial RNA-recognition motif domain 2 (RRM2) in amyotrophic lateral sclerosis (ALS)/frontotemporal lobar degeneration. However, the molecular basis for how this domain links to the conformation and function of TDP-43 is unclear. Previous crystal analyses have documented that the RRM2-DNA complex dimerizes under acidic and high salt conditions, mediated by the intermolecular hydrogen bonds of Glu246-Ile249 and Asp247-Asp247. The aims of this study were to investigate the roles of Glu246 and Asp247 in the molecular assembly of RRM2 under physiological conditions, and to evaluate their potential use as markers for TDP-43 misfolding due to the aberrantly exposed dimer interface. Unexpectedly, gel filtration analyses showed that, regardless of DNA interaction, the RRM2 domain remained as a stable monomer in phosphate-buffered saline. Studies using substitution mutants revealed that Glu246 and, especially, Asp247 played a crucial role in preserving the functional RRM2 monomers. Substitution to glycine at Glu246 or Asp247 induced the formation of fibrillar oligomers of RRM2 accompanied by the loss of DNA-binding affinity, which also affected the conformation and the RNA splicing function of full-length TDP-43. A novel monoclonal antibody against peptides containing Asp247 was found to react with TDP-43 inclusions of ALS patients and mislocalized cytosolic TDP-43 in cultured cells, but not with nuclear wild-type TDP-43. Our findings indicate that Glu246 and Asp247 play pivotal roles in the proper conformation and function of TDP-43. In particular, Asp247 should be studied as a molecular target with an aberrant conformation related to TDP-43 proteinopathy.
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Project description:The degradation of TNFα mRNA is critical for restricting TNFα synthesis and involves a constitutive decay element (CDE) in the 3’ untranslated region of the mRNA. We demonstrate that the active CDE is a stem-loop RNA motif that is recognized by the RNA-binding protein Roquin. Deep sequencing of Roquin-associated mRNAs identified CDE-containing mRNAs as the primary targets of Roquin on a transcriptome-wide scale.
2013-05-15 | GSE44775 | GEO
Project description:The magnitude of the human antibody response to viral antigens is highly variable. To explore the human genetic contribution to this variability, we performed genome-wide association studies of the immunoglobulin G response to 14 pathogenic viruses in 2,363 immunocompetent adults. Significant associations were observed in the major histocompatibility complex region on chromosome 6 for influenza A virus, Epstein-Barr virus, JC polyomavirus, and Merkel cell polyomavirus. Using local imputation and fine mapping, we identified specific amino acid residues in human leucocyte antigen (HLA) class II proteins as the most probable causal variants underlying these association signals. Common HLA-DRβ1 haplotypes showed virus-specific patterns of humoral-response regulation. We observed an overlap between variants affecting the humoral response to influenza A and EBV and variants previously associated with autoimmune diseases related to these viruses. The results of this study emphasize the central and pathogen-specific role of HLA class II variation in the modulation of humoral immune response to viral antigens in humans.
| S-EPMC4667104 | biostudies-literature