scholarly journals Rapid evolution of bacterial AB5 toxin B subunits independent of A subunits: sialic acid binding preferences correlate with host range and toxicity

2021 ◽  
Author(s):  
Naazneen Khan ◽  
Aniruddha Sasmal ◽  
Zahra Khedri ◽  
Patrick Secrest ◽  
Andrea Verhagen ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Host Range ◽  
Rapid Evolution ◽  
Etiologic Agent ◽  
Poor Correlation ◽  
Acetylneuraminic Acid ◽  
Toxin Binding ◽  
B Subunit ◽  
B Subunits ◽  
Typhoid Toxin

Cytotoxic A subunits of bacterial AB5 toxins enter the cytosol following B subunit binding to host cell glycans. We report that A subunit phylogeny evolves independently of B subunits and suggest a future B subunit nomenclature based on species name. Phylogenetic analysis of B subunits that bind sialic acids (Sias) with homologous molecules in databases also show poor correlation with phylogeny. These data indicate ongoing lateral gene transfers between species, with mixing of A and B subunits. Some B subunits are not even associated with A subunits e.g., YpeB of Yersinia pestis, the etiologic agent of plague epidemics. Plague cannot be eradicated because of Y. pestis adaptability to numerous hosts. YpeB shares 58% identity/79% similarity with the homo-pentameric B subunit of E. coli Subtilase cytotoxin, and 48% identity/68% similarity with the B subunit of S. Typhi typhoid toxin. We previously showed selective binding of B5 pentamers to a sialoglycan microarray, with Sia preferences corresponding to hosts e.g., N-acetylneuraminic acid (Neu5Ac; prominent in humans) or N-glycolylneuraminic acid (Neu5Gc; prominent in ruminant mammals and rodents). Consistent with much broader host range of Y. pestis, YpeB binds all mammalian sialic acid types, except for 4-O-acetylated ones. Notably, YpeB alone causes dose-dependent cytotoxicity, abolished by a mutation (Y77F) eliminating Sia recognition, suggesting cell proliferation and death via lectin-like cross-linking of cell surface sialoglycoconjugates. These findings help explain the host range of Y. pestis and could be important for pathogenesis. Overall, our data indicate ongoing rapid evolution of both host Sias and pathogen toxin-binding properties.

scholarly journals The Buzz about ADP-Ribosylation Toxins from Paenibacillus larvae, the Causative Agent of American Foulbrood in Honey Bees

Toxins ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 151
Author(s):  
Julia Ebeling ◽  
Anne Fünfhaus ◽  
Elke Genersch
Keyword(s):  
Virulence Factors ◽  
Structural Similarity ◽  
Paenibacillus Larvae ◽  
American Foulbrood ◽  
Rho Proteins ◽  
Experimental Proof ◽  
Host Interactions ◽  
B Subunit ◽  
Cellular Target ◽  
B Subunits

The Gram-positive, spore-forming bacterium Paenibacillus larvae is the etiological agent of American Foulbrood, a highly contagious and often fatal honey bee brood disease. The species P. larvae comprises five so-called ERIC-genotypes which differ in virulence and pathogenesis strategies. In the past two decades, the identification and characterization of several P. larvae virulence factors have led to considerable progress in understanding the molecular basis of pathogen-host-interactions during P. larvae infections. Among these virulence factors are three ADP-ribosylating AB-toxins, Plx1, Plx2, and C3larvin. Plx1 is a phage-born toxin highly homologous to the pierisin-like AB-toxins expressed by the whites-and-yellows family Pieridae (Lepidoptera, Insecta) and to scabin expressed by the plant pathogen Streptomyces scabiei. These toxins ADP-ribosylate DNA and thus induce apoptosis. While the presumed cellular target of Plx1 still awaits final experimental proof, the classification of the A subunits of the binary AB-toxins Plx2 and C3larvin as typical C3-like toxins, which ADP-ribosylate Rho-proteins, has been confirmed experimentally. Normally, C3-exoenzymes do not occur together with a B subunit partner, but as single domain toxins. Interestingly, the B subunits of the two P. larvae C3-like toxins are homologous to the B-subunits of C2-like toxins with striking structural similarity to the PA-63 protomer of Bacillus anthracis.

scholarly journals The fate of orally administered sialic acid: First insights from patients with N-acetylneuraminic acid synthase deficiency and control subjects

2021 ◽  
Vol 28 ◽  
pp. 100777
Author(s):  
Christel Tran ◽  
Licia Turolla ◽  
Diana Ballhausen ◽  
Sandrine Cornaz Buros ◽  
Tony Teav ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Acetylneuraminic Acid ◽  
Control Subjects ◽  
And Control

scholarly journals Biochemical and structural characterization of the novel sialic acid-binding site of Escherichia coli heat-labile enterotoxin LT-IIb

2016 ◽  
Vol 473 (21) ◽  
pp. 3923-3936 ◽  
Author(s):  
Dani Zalem ◽  
João P. Ribeiro ◽  
Annabelle Varrot ◽  
Michael Lebens ◽  
Anne Imberty ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Binding Site ◽  
Cholera Toxin ◽  
Carbohydrate Binding ◽  
Type I ◽  
Type Ii ◽  
E Coli ◽  
B Subunit ◽  
Heat Labile ◽  
B Subunits

The structurally related AB5-type heat-labile enterotoxins of Escherichia coli and Vibrio cholerae are classified into two major types. The type I group includes cholera toxin (CT) and E. coli LT-I, whereas the type II subfamily comprises LT-IIa, LT-IIb and LT-IIc. The carbohydrate-binding specificities of LT-IIa, LT-IIb and LT-IIc are distinctive from those of cholera toxin and E. coli LT-I. Whereas CT and LT-I bind primarily to the GM1 ganglioside, LT-IIa binds to gangliosides GD1a, GD1b and GM1, LT-IIb binds to the GD1a and GT1b gangliosides, and LT-IIc binds to GM1, GM2, GM3 and GD1a. These previous studies of the binding properties of type II B-subunits have been focused on ganglio core chain gangliosides. To further define the carbohydrate binding specificity of LT-IIb B-subunits, we have investigated its binding to a collection of gangliosides and non-acid glycosphingolipids with different core chains. A high-affinity binding of LT-IIb B-subunits to gangliosides with a neolacto core chain, such as Neu5Gcα3- and Neu5Acα3-neolactohexaosylceramide, and Neu5Gcα3- and Neu5Acα3-neolactooctaosylceramide was detected. An LT-IIb-binding ganglioside was isolated from human small intestine and characterized as Neu5Acα3-neolactohexaosylceramide. The crystal structure of the B-subunit of LT-IIb with the pentasaccharide moiety of Neu5Acα3-neolactotetraosylceramide (Neu5Ac-nLT: Neu5Acα3Galβ4GlcNAcβ3Galβ4Glc) was determined providing the first information for a sialic-binding site in this subfamily, with clear differences from that of CT and LT-I.

scholarly journals N-Glycolylneuraminic Acid in Animal Models for Human Influenza A Virus

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 815
Author(s):  
Cindy M. Spruit ◽  
Nikoloz Nemanichvili ◽  
Masatoshi Okamatsu ◽  
Hiromu Takematsu ◽  
Geert-Jan Boons ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Animal Models ◽  
Influenza A ◽  
Influenza Virus Infection ◽  
Influenza Viruses ◽  
Upper Respiratory Tract ◽  
Human Influenza ◽  
Influenza A Viruses ◽  
Sialic Acid Content ◽  
Acetylneuraminic Acid

The first step in influenza virus infection is the binding of hemagglutinin to sialic acid-containing glycans present on the cell surface. Over 50 different sialic acid modifications are known, of which N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc) are the two main species. Animal models with α2,6 linked Neu5Ac in the upper respiratory tract, similar to humans, are preferred to enable and mimic infection with unadapted human influenza A viruses. Animal models that are currently most often used to study human influenza are mice and ferrets. Additionally, guinea pigs, cotton rats, Syrian hamsters, tree shrews, domestic swine, and non-human primates (macaques and marmosets) are discussed. The presence of NeuGc and the distribution of sialic acid linkages in the most commonly used models is summarized and experimentally determined. We also evaluated the role of Neu5Gc in infection using Neu5Gc binding viruses and cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMAH)-/- knockout mice, which lack Neu5Gc and concluded that Neu5Gc is unlikely to be a decoy receptor. This article provides a base for choosing an appropriate animal model. Although mice are one of the most favored models, they are hardly naturally susceptible to infection with human influenza viruses, possibly because they express mainly α2,3 linked sialic acids with both Neu5Ac and Neu5Gc modifications. We suggest using ferrets, which resemble humans closely in the sialic acid content, both in the linkages and the lack of Neu5Gc, lung organization, susceptibility, and disease pathogenesis.

Interaction of Mycoplasma gallisepticum with sialyl glycoproteins

1980 ◽  
Vol 30 (2) ◽  
pp. 353-361
Author(s):  
L R Glasgow ◽  
R L Hill
Keyword(s):  
Sialic Acid ◽  
Mycoplasma Gallisepticum ◽  
Binding Assays ◽  
Molecular Weights ◽  
Acetylneuraminic Acid ◽  
Direct Binding ◽  
Membrane Bound ◽  
Strict Specificity ◽  
Human Glycophorin ◽  
Acid Structure

The binding of several glycoproteins to freshly grown and harvested cells of Mycoplasma gallisepticum was examined. Only human glycophorin, the major sialoglycoprotein of the erythrocyte membrane, bound tightly as judged by direct binding assays with 125I-labeled glycoproteins. Neuraminidase-treated glycophorin did not bind, suggesting that binding is mediated through sialic acid groups. Although other sialoglycoproteins did not appear to bind M. gallisepticum by direct binding assays, some inhibited the binding of glycophorin. The best inhibitors had a mucin-like structure, with high molecular weights and high sialic acid contents. N-acetylneuraminic acid appeared to be the favored sialic acid structure for binding, but there was no strict specificity for its anomeric linkage. Neuraminidase activity could not be detected on the surface of M. gallisepticum, suggesting that this enzyme is not involved in the mechanism of adherence of sialoglycoproteins. Binding of sialoglycoproteins was time dependent, however, and markedly diminished with increasing ionic strength, but was largely unaffected between pH 4 and 9.

Porcine Sugar Nucleotide: Glycoprotein Glycosyltransferases. I. Blood Serum and Liver Sialyltransferase

1971 ◽  
Vol 49 (7) ◽  
pp. 829-837 ◽  
Author(s):  
Roger L. Hudgin ◽  
Harry Schachter
Keyword(s):  
Sialic Acid ◽  
High Speed ◽  
Liver Homogenate ◽  
Acetone Powder ◽  
Acid Glycoprotein ◽  
Acetylneuraminic Acid ◽  
Pork Liver ◽  
Terminal Galactose ◽  
And Function ◽  
Powder Extract

The properties of CMP-N acetylneuraminic acid: glycoprotein sialyltransferase have been studied in pork serum, a crude pork liver homogenate, and a soluble acetone powder extract prepared from pork liver. Whereas the crude liver homogenate enzyme is activated by the detergent Triton X-100, this detergent has no effect on the activities of either serum or acetone powder extract; since high-speed centrifugation does not sediment the enzyme activities of the latter two preparations, it is concluded that they are soluble. Comparison of the membrane-bound and soluble liver enzymes indicates that the membrane modifies kinetic behavior only to a limited extent. In both liver and serum, a single sialyltransferase is responsible for incorporation of sialic acid into α1-acid glycoprotein, fetuin, and N-acetyllactosamine, and sialic acid incorporation occurs whenever a terminal galactose linked (β, 1 → 4) to a penultimate N-acetylglucosamine is presented to the enzyme. Although the serum enzyme resembles the liver enzyme, both the source and function of serum sialyltransferase are unknown.

scholarly journals Shiga toxin–binding site for host cell receptor GPP130 reveals unexpected divergence in toxin-trafficking mechanisms

2013 ◽  
Vol 24 (15) ◽  
pp. 2311-2318 ◽  
Author(s):  
Somshuvra Mukhopadhyay ◽  
Brendan Redler ◽  
Adam D. Linstedt
Keyword(s):  
Shiga Toxin ◽  
Transmembrane Domain ◽  
Cell Receptor ◽  
Toxin B ◽  
Toxin Binding ◽  
B Subunit ◽  
Host Cell Receptor ◽  
Developed World ◽  
Trafficking Receptor ◽  
Shed Light

Shiga toxicosis is caused by retrograde trafficking of one of three types of Shiga toxin (STx), STx, STx1, or STx2. Trafficking depends on the toxin B subunits, which for STx and STx1 are identical and bind GPP130, a manganese (Mn)-sensitive intracellular trafficking receptor. Elevated Mn down-regulates GPP130, rendering STx/STx1 harmless. Its effectiveness against STx2, however, which is a serious concern in the developed world, is not known. Here we show that Mn-induced GPP130 down-regulation fails to block STx2 trafficking. To shed light on this result, we tested the purified B subunit of STx2 for binding to GPP130 and found that it failed to interact. We then mapped residues at the interface of the GPP130-STx/STx1 complex. In GPP130, binding mapped to a seven-residue stretch in its lumenal stem domain next to the transmembrane domain. This stretch was required for STx/STx1 transport. In STx/STx1, binding mapped to a histidine–asparagine pair on a surface-exposed loop of the toxin B subunit. Significantly, these residues are not conserved in STx2, explaining the lack of effectiveness of Mn against STx2. Together our results imply that STx2 uses an evolutionarily distinct trafficking mechanism and that Mn as a potential therapy should be focused on STx/STx1 outbreaks, which account for the vast majority of cases worldwide.

Sign in / Sign up

Export Citation Format

Share Document