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PubMed1998

NMR solution structure of the periplasmic chaperone FimC.

The NMR structure of the 205-residue periplasmic chaperone FimC is presented. This protein consists of two globular domains with immunoglobulin-like folds connected by a 15-residue linker peptide. The relative orientation of the two domains is defined by hydrophobic contacts and an interdomain salt bridge. FimC mediates the assembly of type-1 pili, which are filamentous surface organelles of uropathogenic Escherichia coli strains that enable the bacteria to attach to host cell surfaces and persist in macrophages. The availability of the NMR structure of FimC provides a new basis for rational design of drugs against infections by uropathogenic bacteria.

Amino Acid Sequence↗

PubMedDate not supplied

Cephalosporin antibiotics can be modified to inhibit human leukocyte elastase.

Several laboratories, including our own have reported the synthesis and activity of certain low relative molecular mass inhibitors of mammalian serine proteases, especially human leukocyte elastase (HLE, EC 3.4.21.37), an enzyme whose degradative activity on lung elastin has been implicated as a major causative factor in the induction of pulmonary emphysema, and which is present in the azurophil granules of human polymorphonuclear leukocytes (PMN). Normally, these granules fuse with phagosomes containing engulfed foreign material (such as bacteria), and HLE, in combination with other lysosomal enzymes, catabolizes the particles. Under certain pathological conditions, however, PMN become attached to host protein (elastin fibres, basement membrane, connective tissue, immune complexes), and in response to this adherence, the granules may fuse with the PMN outer membrane and release their contents, including HLE, directly onto the tissue. Besides emphysema, HLE may also contribute to the pathogenesis of disease states such as adult respiratory distress syndrome, and its potential involvement in rheumatoid arthritis makes HLE inhibitors of considerable interest. It is known that cephalosporin antibiotics (for example, cephalothin (compound I, Table 2)) are acylating inhibitors of bacterial serine proteases which help synthesize the cell wall by performing a transpeptidation reaction on a peptidyl substrate bearing a D-Ala-D-Ala terminus. We now report that neutral cephalosporins (that is, compounds not bearing a free carboxyl at position C-4) can be modified to become potent time-dependent inhibitors of HLE.

Cephalosporins↗

PubMed2001

Crystal structure of the retaining galactosyltransferase LgtC from Neisseria meningitidis in complex with donor and acceptor sugar analogs.

Many bacterial pathogens express lipooligosaccharides that mimic human cell surface glycoconjugates, enabling them to attach to host receptors and to evade the immune response. In Neisseria meningitidis, the galactosyltransferase LgtC catalyzes a key step in the biosynthesis of lipooligosaccharide structure by transferring alpha-d-galactose from UDP-galactose to a terminal lactose. The product retains the configuration of the donor sugar glycosidic bond; LgtC is thus a retaining glycosyltranferase. We report the 2 A crystal structures of the complex of LgtC with manganese and UDP 2-deoxy-2-fluoro-galactose (a donor sugar analog) in the presence and absence of the acceptor sugar analog 4'-deoxylactose. The structures, together with results from site-directed mutagenesis and kinetic analysis, give valuable insights into the unique catalytic mechanism and, as the first structure of a glycosyltransferase in complex with both the donor and acceptor sugars, provide a starting point for inhibitor design.

Amino Acid Sequence↗

PubMed2005

Three-dimensional structure of the bacteriophage P22 tail machine.

The tail of the bacteriophage P22 is composed of multiple protein components and integrates various biological functions that are crucial to the assembly and infection of the phage. The three-dimensional structure of the P22 tail machine determined by electron cryo-microscopy and image reconstruction reveals how the five types of polypeptides present as 51 subunits are organized into this molecular machine through twelve-, six- and three-fold symmetry, and provides insights into molecular events during host cell attachment and phage DNA translocation.

Amino Acid Sequence↗

PubMed2003

Regulation, secretion and activity of type III-secreted proteins of enterohaemorrhagic Escherichia coli O157.

Enterohaemorrhagic Escherichia coli (EHEC) O157:H7 causes gastrointestinal disease with the potential for life-threatening sequelae. Although Shiga-like toxins are responsible for much of the serious pathology in humans, the bacterium also possesses a type III protein secretion system that is responsible for intimate attachment to host intestinal mucosa. This sophisticated interaction requires co-ordination that is governed by environmental and genetic factors. Ongoing research supports the following model for how EHEC enables and controls this process: (i) specific environmental cues that are present in the host result in the expression of a number of adhesins, including fimbriae, which allow the initial binding to the mucosal surface. The same conditions support the expression of the basal type III secretion apparatus; (ii) targeting and assembly of the translocon requires both an mRNA signal and chaperones, with coupled translation and secretion of translocon proteins, EspA, B and D; (iii) opening up of a conduit between the bacterium and host cell releases a cytoplasmic pool of effector proteins. A consequence of this is increased expression of particular effector proteins. Potentially, different proteins could be released into the cell at different times or have activities modulated with time; (iv) intimate contact between the translocated intimin receptor (Tir) and the bacterial surface factor intimin requires translocon expression to be down-regulated and translocon filaments to be lost. Fluorescent protein fusions allow contact-mediated regulation and protein targeting through the type III secretion system to be studied in detail.

Adhesins, Bacterial↗

PubMed1997

Participation of myosin in gliding motility and host cell invasion by Toxoplasma gondii.

Toxoplasma gondii is an obligate intracellular parasite that actively invades mammalian cells using a unique form of gliding motility that critically depends on actin filaments in the parasite. To determine if parasite motility is driven by a myosin motor, we examined the distribution of myosin and tested the effects of specific inhibitors on gliding and host cell invasion. A single 90 kDa isoform of myosin was detected in parasite lysates using an antisera that recognizes a highly conserved myosin peptide. Myosin was localized in T. gondii beneath the plasma membrane in a circumferential pattern that overlapped with the distribution of actin. The myosin ATPase inhibitor, butanedione monoxime (BDM), reversibly inhibited gliding motility across serum-coated slides. The myosin light-chain kinase inhibitor, KT5926, also blocked parasite motility and greatly reduced host cell attachment; however, these effects were primarily caused by its ability to block the secretion of microneme proteins, which are involved in cell attachment. In contrast, while BDM partially reduced cell attachment, it prevented invasion even under conditions in which microneme secretion was not affected, indicating a potential role for myosin in cell entry. Collectively, these results indicate that myosin(s) probably participate(s) in powering gliding motility, a process that is essential for cell invasion by T. gondii.

Actins↗

PubMed1999

Type IV pili of pathogenic Neisseriae elicit cortical plaque formation in epithelial cells.

The pathogenic Neisseriae Neisseria meningitidis and Neisseria gonorrhoeae, initiate colonization by attaching to host cells using type IV pili. Subsequent adhesive interactions are mediated through the binding of other bacterial adhesins, in particular the Opa family of outer membrane proteins. Here, we have shown that pilus-mediated adhesion to host cells by either meningococci or gonococci triggers the rapid, localized formation of dramatic cortical plaques in host epithelial cells. Cortical plaques are enriched in both components of the cortical cytoskeleton and a subset of integral membrane proteins. These include: CD44v3, a heparan sulphate proteoglycan that may serve as an Opa receptor; EGFR, a receptor tyrosine kinase; CD44 and ICAM-1, adhesion molecules known to mediate inflammatory responses; f-actin; and ezrin, a component that tethers membrane components to the actin cytoskeleton. Genetic analyses reveal that cortical plaque formation is highly adhesin specific. Both pilE and pilC null mutants fail to induce cortical plaques, indicating that neisserial type IV pili are required for cortical plaque induction. Mutations in pilT, a gene required for pilus-mediated twitching motility, confer a partial defect in cortical plaque formation. In contrast to type IV pili, many other neisserial surface structures are not involved in cortical plaque induction, including Opa, Opc, glycolipid GgO4-binding adhesins, polysialic acid capsule or a particular lipooligosaccharide variant. Furthermore, it is shown that type IV pili allow gonococci to overcome the inhibitory effect of heparin, a soluble receptor analogue, on gonococcal invasion of Chang and A431 epithelial cells. These and other observations strongly suggest that type IV pili play an active role in initiating neisserial infection of the mucosal surface in vivo. The functions of type IV pili and other neisserial adhesins are discussed in the specific context of the mucosal microenvironment, and a multistep model for neisserial colonization of mucosal epithelia is proposed.

Animals↗

PubMed2000

Evidence for donor strand complementation in the biogenesis of Haemophilus influenzae haemagglutinating pili.

Haemophilus influenzae haemagglutinating pili are surface appendages that promote attachment to host cells and facilitate respiratory tract colonization, an essential step in the pathogenesis of disease. In contrast to other well-characterized forms of pili, H. influenzae haemagglutinating pili are two-stranded helical structures. Nevertheless, haemagglutinating pili are assembled by a pathway that involves a periplasmic chaperone and an outer membrane usher, analogous to the prototype pathway involved in the biogenesis of Escherichia coli P pili. In this study, we performed site-directed mutagenesis of the H. influenzae HifB chaperone and HifA major pilus subunit at positions homologous to sites important for chaperone-subunit interactions and subunit oligomerization in P pili. Mutations at putative subunit binding pocket residues in HifB or at the penultimate tyrosine in HifA abolished formation of HifB-HifA periplasmic complexes, whereas mutations at the -14 glycine in HifA had no effect on HifB-HifA interactions but abrogated HifA oligomerization. To define further the constraints of the interaction between HifA and HifB, we examined the interchangeability of pilus gene cluster components from H. influenzae type b strain Eagan (hifA-hifEEag) and the related H. influenzae biogroup aegyptius strain F3031 (hifA-hifEF3031). Functional pili were assembled both with HifAEag and the strain F3031 gene cluster and with HifAF3031 and the strain Eagan gene cluster, underscoring the flexibility of the H. influenzae chaperone/usher pathway in incorporating HifA subunits with significant sequence diversity. To gain additional insight into the interactive surfaces of HifA and HifB, we aligned HifA sequences from 20 different strains and then modelled the HifA structure based on the recently crystallized PapD-PapK complex. Analysis of the resulting structure revealed high levels of sequence conservation in regions predicted to interact with HifB, and maximal sequence diversity in regions potentially exposed on the surface of assembled pili. These results suggest broad applicability of structure-function relationships identified in studies of P pili, including the concepts of donor strand complementation and donor strand exchange. In addition, they provide insight into the structure of HifA and suggest a basis for antigenic variation in H. influenzae haemagglutinating pili.

Amino Acid Motifs↗

PubMed2001

Escherichia coli P fimbriae utilize the Toll-like receptor 4 pathway for cell activation.

Fimbriae mediate bacterial attachment to host cells and provide a mechanism for tissue attack. They activate a host response by delivery of microbial products such as lipopolysaccharide (LPS) or through direct fimbriae-dependent signalling mechanisms. By coupling to glycosphingolipid (GSL) receptors, P fimbriae trigger cytokine responses in CD14 negative host cells. Here we show that P fimbriae utilize the Toll-like receptor 4 (TLR4)-dependent pathway to trigger mucosal inflammation. Escherichia coli strains expressing P fimbriae as their only virulence factor stimulated chemokine and neutrophil responses in the urinary tract of TLR4 proficient mice, but TLR4 defective mice failed to respond to infection. Mucosal cells were CD14 negative but expressed several TLR species including TLR4, and TLR4 protein was detected. Infection with P fimbriated bacteria stimulated an increase in TLR4 mRNA levels. The activation signal did not involve the LPS-CD14 pathway and was independent of lipid A myristoylation, as shown by mutational inactivation of the msbB gene. Co-staining experiments revealed that TLR4 and the GSL receptors for P fimbriae co-localized in the cell membrane. The results demonstrate that P fimbriae activate epithelial cells by means of a TLR4-dependent signalling pathway, and suggest that GSL receptors for P fimbriae can recruit TLR4 as co-receptors.

Animals↗

PubMed2002

A polymer with a backbone of 3-deoxy-D-glycero-D-galacto-non-2-ulopyranosonic acid, a teichuronic acid, and a beta-glucosylated ribitol teichoic acid in the cell wall of plant pathogenic Streptomyces sp. VKM Ac-2124.

Structures of cell wall anionic polymers of the strain Streptomyces sp. VKM Ac-2124, a causative agent of potato scab, which is phylogenetically the closest to plant pathogenic species S. setonii and S. caviscabies, were studied. The strain contains three anionic glycopolymers, viz., a teichuronic acid with a disaccharide repeating unit -->6)-alpha-d-Glcp-(1-->4)-beta-d-ManpNAc3NAcA-(1-->, a beta-glucosylated polymer of 3-deoxy-d-glycero-d-galacto-non-2-ulopyranosonic acid (Kdn), and a beta-glucosylated 1,5-poly(ribitol phosphate). The strain studied is the second representative of plant pathogenic streptomycetes inducing potato scab disease, the cell wall anionic polymers of which were shown to contain a Kdn-polymer. Presumably, the presence of Kdn-containing structures in the surface regions of pathogens is essential for their efficient attachment to host plant cells.

Cell Wall↗

PubMed2000

Problem pulmonary pathogens: Pseudomonas aeruinosa.

Pseudomonas aeruginosa is a common and highly lethal agent of nosocomial pneumonia, especially among patients receiving mechanical ventilation. It is widespread in the environment and commonly recovered from water in nature and in hospital settings. P. aeruginosa is endowed with a formidable array of virulence factors that facilitate attachment to host cells, tissue invasion, and systemic disease. It is intrinsically resistant to many commonly used antibiotics due to a complex variety of mechanisms that we will briefly review. Recent advances in the understanding of the molecular biology of this organism have shed considerable light on its ability to form biofilms, which facilitate adherence especially in cystic fibrosis patients, and confer resistance to clearance by host immune mechanisms and antimicrobial killing. Treatment studies have demonstrated a significant risk of emergence of resistance during therapy with a variety of agents. Several studies suggest that two drugs are better than one for therapy of serious infections, although dual therapy does not always prevent emergence of resistant strains.

Journal Article↗

PubMed2003

Pseudomonas aeruginosa infections in the intensive care unit.

Pseudomonas aeruginosa is a common and highly lethal agent of nosocomial infection, especially among intensive care unit patients. It is widespread in the environment and commonly recovered from water in nature and in hospital settings. P. aeruginosa is endowed with a formidable array of virulence factors that facilitate attachment to host cells, tissue invasion, and systemic disease. It is intrinsically resistant to many commonly employed antibiotics due to a complex variety of mechanisms briefly reviewed here. Resistance to fluoroquinolones appears to be increasing particularly rapidly. Recent advances in the understanding of the molecular biology of this organism have shed considerable light on its ability to form biofilms, which facilitate adherence, especially in cystic fibrosis patients, and confer resistance to clearance by host immune mechanisms and antimicrobial killing. Treatment studies have demonstrated a significant risk of emergence of resistance during therapy with a variety of agents. Several studies suggest that two drugs are better than one for therapy of serious infections, although dual therapy does not always prevent emergence of resistant strains. The sequencing of the genome will lead to new understanding of pathogenesis and may identify new drug targets.

Journal Article↗

PubMed1969

The proteins of bacteriophage M13.

Particles of the small filamentous coliphage M13 contain not only the major coat protein, which is the product of phage gene 8, but also a minor coat protein, the A protein, which is the product of gene 3. The A protein has a molecular weight of approximately 70,000 daltons, is present in one copy per virion, and is responsible for phage attachment to host cells. Also associated with purified M13 particles is a minor quantity of very small proteinaceous material, but its origin as a phage-coded product has not been demonstrated. At least five phage-specific proteins, including the two coat proteins, are present in appreciable quantities in M13-infected cells. The principal phage protein synthesized is the product of gene 5, which is responsible for phage single-stranded DNA synthesis. This protein has a molecular weight of about 8,000 daltons. Its precise function in DNA synthesis is not yet known. Phage proteins are synthesized at nearly normal rates in cells in which replication of phage double-stranded DNA is blocked by gene 2 mutations. This result suggests that the initial double-stranded DNA molecule serves as the principal template, perhaps the only template, for phage messenger RNA synthesis.

Coliphages↗

PubMed1978

Proteins conferred by the virulence-specifying plasmid of Agrobacterium tumefaciens C-58.

Membrane-associated and periplasmic proteins of Agrobacterium tumefaciens C-58 were compared with those from avirulent (nontumrigenic) derivative strains by slab and two-dimensional gel electrophoresis. Two proteins (Per-I and Per-2), with a molecular weight of 37,500 and 37,300, respectively, were detected in the supernatant fraction of cells of strain C-58 treated with EDTA and lysozyme in which a 117-megadalton plasmid confers virulence on the organism. The same proteins are missing in an avirulent plasmid-free derivative of C-58. When this derivative is mated with C-58, the resulting transconjugants regain the large C-58 plasmid together with the restoration of virulence and the expression of Per-1 and Per-2 proteins. When the transconjugants were cured of their plasmid, they concomitantly lost their virulence and Per-1 and Per-2. The functional roles of these proteins are unknown, but they are associated with the outer membrane and periplasmic fraction of the Agrobacterium cell. If directly involved in tumorigenesis, these proteins are not the sole determinants of tumorigenicity because they are synthesized in an avirulent derivative of C-58 that carries a deletion in the plasmid in the region conferring the tumorigenic phenotype. These results strongly suggest that the Per-1 and Per-2 proteins are plasmid-coded gene products. The possible roles of these proteins in specifying host range and host-cell attachment are also discussed.

Bacterial Proteins↗

PubMed1989

A plasmid-encoded regulatory gene, rns, required for expression of the CS1 and CS2 adhesins of enterotoxigenic Escherichia coli.

To be virulent, enterotoxigenic Escherichia coli (ETEC) must produce a toxin and a pilus-like structure that mediates specific attachment to host tissue. Expression of two of these specific adherence structures, CS1 and CS2, requires the presence of a plasmid in an ETEC strain of a particular serotype and biotype. We show here that this plasmid does not contain the structural gene for a pilin protein, as previously believed. Instead we have identified a plasmid-encoded gene called rns that is required for expression of CS1 or CS2 colonization factor antigens and for adhesion. The rns gene, defined by two separately isolated insertion mutations, produces a 26-kDa protein when transcribed and translated in vitro. At the protein level the rns gene product is homologous to AraC, a positive regulator of the arabinose operon of enteric bacteria, and to RhaR and RhaS, which regulate the rhamnose operon of E. coli. The homology of the Rns protein to AraC is localized to regions that are believed to bind to DNA. Moreover, the sequence of one of these homologous regions is consistent with a DNA binding helix-turn-helix motif. The average G + C content of E. coli DNA is 50%; yet the rns gene contains only 28% G + C, suggesting that it was acquired from some other organism.

Adhesins, Escherichia coli↗

PubMed1997

Evolution subverting essentiality: dispensability of the cell attachment Arg-Gly-Asp motif in multiply passaged foot-and-mouth disease virus.

Aphthoviruses use a conserved Arg-Gly-Asp triplet for attachment to host cells and this motif is believed to be essential for virus viability. Here we report that this triplet-which is also a widespread motif involved in cell-to-cell adhesion-can become dispensable upon short-term evolution of the virus harboring it. Foot-and-mouth disease virus (FMDV), which was multiply passaged in cell culture, showed an altered repertoire of antigenic variants resistant to a neutralizing monoclonal antibody. The altered repertoire includes variants with substitutions at the Arg-Gly-Asp motif. Mutants lacking this sequence replicated normally in cell culture and were indistinguishable from the parental virus. Studies with individual FMDV clones indicate that amino acid replacements on the capsid surface located around the loop harboring the Arg-Gly-Asp triplet may mediate in the dispensability of this motif. The results show that FMDV quasispecies evolving in a constant biological environment have the capability of rendering totally dispensable a receptor recognition motif previously invariant, and to ensure an alternative pathway for normal viral replication. Thus, variability of highly conserved motifs, even those that viruses have adapted from functional cellular motifs, can contribute to phenotypic flexibility of RNA viruses in nature.

Aphthovirus↗

PubMed1995

Genomic cloning, characterization, and functional analysis of the major surface adhesin WI-1 on Blastomyces dermatitidis yeasts.

WI-1 is a 120-kDa surface protein adhesin on Blastomyces dermatitidis yeasts that binds CD18 and CD14 receptors on human macrophages. We isolated and analyzed a clone of genomic WI-1 to characterize this key adherence mechanism of the yeast. The 9.3-kilobase insert contains an open reading frame of 3438 nucleotides and no introns. The amino acid sequence of native WI-1 matches the deduced sequence of genomic WI-1 at positions 757-769, 901-913, and 1119-1138, demonstrating the cloned gene is authentic WI-1. The complete coding sequence has 30 highly conserved repeats of 24 amino acids arrayed in tandem in two noncontiguous regions of the protein. The repeat sequence is homologous to the Yersiniae adhesin invasin, the C terminus displays an epidermal growth factor-like domain, and the N terminus has a short hydrophobic sequence that may be a membrane-spanning domain. The tandem repeats are predicted to be at the exposed surface of the protein, thereby explaining the adhesive properties of WI-1. The WI-1 promoter contains a CAAT box (nucleotide positions 2287-2290), TATA box (2380-2385), and CT motif (2399-2508). Transcription is initiated within the CT motif at nucleotide 2431. A 5.5-kilobase subclone containing the full coding sequence of WI-1 was expressed as a histidine-tagged fusion protein in Escherichia coli. Recombinant WI-1 has the expected molecular mass of 120 kDa, is strongly recognized in Western blots by rabbit anti-WI-1 antiserum, and binds human macrophage receptors in the same manner as native WI-1. This work clarifies a key adherence mechanism of B. dermatitidis and will permit further analysis of WI-1-mediated attachment to host cells, receptors, and extracellular matrix.

Amino Acid Sequence↗

PubMed2005

A novel galectin-like domain from Toxoplasma gondii micronemal protein 1 assists the folding, assembly, and transport of a cell adhesion complex.

Immediately prior to invasion Toxoplasma gondii tachyzoites release a large number of micronemal proteins (TgMICs) that participate in host cell attachment and penetration. The TgMIC4-MIC1-MIC6 complex was the first to be identified in T. gondii and has been recently shown to be critical in invasion. This study establishes that the N-terminal thrombospondin type I repeat-like domains (TSR1-like) from TgMIC1 function as an independent adhesin as well as promoting association with TgMIC4. Using the newly solved three-dimensional structure of the C-terminal domain of TgMIC1 we have identified a novel Galectin-like fold that does not possess carbohydrate binding properties and redefines the architecture of TgMIC1. Instead, the TgMIC1 Galectin-like domain interacts and stabilizes TgMIC6, which provides the basis for a highly specific quality control mechanism for successful exit from the early secretory compartments and for subsequent trafficking of the complex to the micronemes.

Animals↗