Cellular functions require specific protein-protein interactions that are often mediated by modular domains use binding pockets to engage particular sequence motifs in their partners. Yet, how different members of a domain family select for distinct is not fully understood. The human genome encodes 120 Src homology 2 (SH2) (in 110 proteins), which mediate proteins with diverse phosphotyrosine (pTyr)-containing sequences. structure the SH2 BRDG1 bound peptide revealed pocket was blocked loop...

Phosphorylation of caspase substrates by the protein kinase CK2 may underlie its role in tumorigenesis.

The oral biofilm community consists of >800 microbial species, among which Streptococcus mutans is considered a primary pathogen for dental caries. genomic island TnSmu2 S. comprises >2% the genome. In this study, we demonstrate that harbors gene cluster encoding nonribosomal peptide synthetases (NRPS), polyketide synthases (PKS), and accessory proteins regulators involved in (NRP) (PK) biosynthesis. Interestingly, sequences these genes their organizations locations are highly divergent...

Significance Fusobacterium nucleatum interacts with many oral microbes and has the ability to spread placenta amniotic fluid, promoting preterm birth. Yet, molecular mechanisms underlying polymicrobial interactions, termed coaggregation, by Fusobacteria are poorly understood. Here, we revealed that two-component signal transduction system CarRS regulates expression of genes encoding lysine utilization factors (e.g., KamA) coaggregation factor RadD. Extracellular blocks RadD-mediated binding...

Significance The newly described type IX secretion systems (T9SSs) translocate virulence factors and can mediate specialized gliding motility among bacterial pathogens of the Fibrobacteres–Chlorobi–Bacterioidetes superphylum. We visualized spatial organization T9SS in its native context Porphorymonas gingivalis cell by cryoelectron tomography. exhibits distinct symmetries across envelope: a cytoplasmic complex requiring PorL PorM for assembly 12-fold symmetry; periplasmic composed 18-fold...

Systematic identification of direct protein-protein interactions is often hampered by difficulties in expressing and purifying the corresponding full-length proteins. By taking advantage modular nature many regulatory proteins, we attempted to simplify domain-ligand recognition employed peptide arrays identify such binding events. A group 12 Src homology (SH) 3 domains from eight human proteins (Swiss-Prot ID: SRC, PLCG1, P85A, NCK1, GRB2, FYN, CRK) were used screen a target array composed...

Interbacterial interactions between oral streptococci and actinomyces their adherence to tooth surface the associated host cells are key early events that promote development of complex biofilm referred as dental plaque. These depend largely on a lectin-like activity with Actinomyces oris type 2 fimbria, structure assembled by sortase (SrtC2)-dependent polymerization shaft tip fimbrillins, FimA FimB respectively. To dissect function specific fimbrillins in various processes, we have...

The small ubiquitin-like modifiers (SUMOs) regulate many essential cellular functions. Only one type of SUMO-interacting motif (SIM) has been identified that can extend the β-sheet SUMO as either a parallel or an antiparallel strand. molecular determinants bound orientation and paralogue specificity SIM are unclear. To address this question, we have conducted structural studies SUMO1 in complex with SUMO1-specific binds to high affinity without post-translational modifications using nuclear...

The c-KIT receptor tyrosine kinase mediates the cellular response to stem cell factor (SCF). Whereas activity is important for proliferation of hematopoietic cells, melanocytes and germ uncontrolled contributes growth diverse human tumors. Suppressor cytokine signaling 6 (SOCS6) a member SOCS family E3 ubiquitin ligases that can interact with suppress c-KIT-dependent pathways. Here, we analyzed molecular mechanisms determine SOCS6 substrate recognition. Our results show SH2 domain essential...

In the oral biofilm, ‘mitis’ streptococci are among first group of organisms to colonize tooth surface. Their proliferation is thought be an important factor required for antagonizing growth cariogenic species such as Streptococcus mutans . this study, we used a three-species mixed culture demonstrate that another ubiquitous early colonizing species, Veillonella parvula, can greatly affect outcome competition between pair antagonists S. and gordonii Transcriptome analysis further revealed...

Mutations of the X-linked gene encoding methyl CpG binding protein type 2 (MECP2) are predominant cause Rett syndrome, a severe neurodevelopmental condition that affects primarily females. Previous studies have shown major phenotypic deficits arising from MeCP2-deficiency may be reversible, as delayed reactivation Mecp2 in Mecp2-deficient mice improved aspects their Rett-like phenotype. While encouraging for prospective replacement treatments, it remains unclear whether additional syndrome...

Fusobacterium nucleatum is a key member of the human oral biofilm. It also implicated in preterm birth and colorectal cancer. To facilitate basic studies fusobacterial virulence, we describe here versatile transposon mutagenesis procedure pilot screen for mutants defective biofilm formation. Out 10 independent biofilm-defective isolated, affected genes included homologs Escherichia coli cell division proteins FtsX EnvC, electron transport protein RnfA, four with unknown functions. Next,...

Significance The development of dental plaque biofilm requires specific and sequential molecular interactions between oral bacteria-colonizing host surfaces. Coaggregation early colonizers is crucial to establish an environment suitable for late colonizers. Here, we describe that a surface protein in Gram-positive bacterium not genetically linked the fimbrial gene clusters hijacks polymerization apparatus be displayed on tip. This tip-localized only functions as bona fide cell-to-cell...

Summary Sortase, a cysteine‐transpeptidase conserved in G ram‐positive bacteria, anchors on the cell wall many surface proteins that facilitate bacterial pathogenesis and fitness. Genetic disruption of housekeeping sortase several pathogens reported thus far attenuates virulence, but not growth. Paradoxically, we discovered depletion SrtA was lethal for A ctinomyces oris ; yet, all its predicted wall‐anchored protein substrates ( AcaA ‐ N ) were individually dispensable viability. Using Tn 5...

ABSTRACT Fusobacterium nucleatum is an opportunistic pathogen with four subspecies: (FNN), vincentii (FNV), polymorphum (FNP), and animalis (FNA), each distinct disease potentials. Research on fusobacterial pathogenesis has mainly focused the model strain ATCC 23726 from FNN. However, this narrow focus may overlook significant behaviors of other FNN strains those subspecies, given genetic phenotypic diversity within F. . While highly transformable, most exhibit low transformation efficiency,...

The Gram-negative anaerobe Fusobacterium nucleatum is an oral oncobacterium that promotes colorectal cancer (CRC) development with the amyloid-forming cell surface adhesin FadA integral to CRC tumorigenesis. We describe here molecular genetic studies uncovering a novel mode of metabolic regulation FadA-mediated tumor formation by highly conserved respiratory enzyme known as Rnf complex. First, we show disruption Rnf, via rnfC deletion, significantly reduces level fadA transcript, accompanied...

Abstract Considered a commensal, the Gram‐negative anaerobe Fusobacterium nucleatum is key member of oral microbiome due to its wide range interactions with many microbes. While periodontal pathogenic properties this organism have widely been examined, connotation extra‐oral infections, including preterm birth and colorectal cancer, has now become apparent. Nonetheless, little known about mechanisms pathogenicity associated virulence factors F. , most likely limited genetic tools facile...

The Gram-negative anaerobe Fusobacterium nucleatum is a major producer of hydrogen sulfide (H2S), volatile sulfur compound that causes halitosis. Here, we dissected the genetic determinants H2S production and its role in bacterial fitness virulence this important member oral microbiome. F. possesses four enzymes, CysK1, CysK2, Hly, MegL, presumably metabolize l-cysteine to H2S, CysK1 was previously shown account for most vitro, based on correlations enzymatic activities with gene expression...

The Src homology (SH) 3 domain has been shown recently to bind peptide sequences that lack the canonical PXXP motif. diverse specificity in ligand recognition for a group of 15 SH3 domains now investigated using arrays peptides derived from proline-rich region SH2 domain-containing leukocyte protein 76 kDa (SLP-76). A screen individual or mixed allowed identification number candidate SH3-binding peptides. Although some contain conventional motif, most are devoid such motif and instead...

ABSTRACT Interaction of Actinomyces oris with salivary proline-rich proteins (PRPs), which serve as fimbrial receptors, involves type 1 fimbriae. Encoded by the gene locus fimQ-fimP-srtC1 , fimbria is comprised shaft FimP and tip fimbrillin FimQ. Fimbrial polymerization requires fimbria-specific sortase SrtC1, catalyzes covalent linkage subunits. Using genetics, biochemical methods, electron microscopy, we provide evidence that fimbrillin, FimQ, involved in assembly interaction PRPs....

In Caenorhabditis elegans, ROS generated in response to intestinal infection induces SKN-1, a protective transcription factor homologous nuclear erythroid 2-related 1 or 2 (NRF1/2) mammals. Many factors regulate including the p38 mitogen-activated protein kinase (MAPK) cascade that activates SKN-1 by phosphorylation. this work, another positive regulator of is identified: NIPI-3, Tribbles pseudokinase. NIPI-3 has been reported protect against negatively regulating CCAT enhancer binding...