A role for glycosylated serine‐rich repeat proteins in Gram‐positive bacterial pathogenesis

Lizcano, Anel; Sánchez, Carlos J.; Orihuela, Carlos J.

doi:10.1111/j.2041-1014.2012.00653.x

Cited by 90 publications

(126 citation statements)

References 76 publications

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“…These polymers, as with WTA, are implicated in adhesion, immune evasion, colonization, biofilm formation, and virulence in Gram-positive bacteria (reviewed in ref. 46), which presents an interesting parallel between the two cell surface polymer decorating systems. By contrast, TarS (an inverting GT-A) is not predicted to contain domain DUF1975.…”

Section: Discussionmentioning

confidence: 99%

Structure and mechanism ofStaphylococcus aureusTarM, the wall teichoic acid α-glycosyltransferase

Sobhanifar

Worrall

Gruninger

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Unique to Gram-positive bacteria, wall teichoic acids are anionic glycopolymers cross-stitched to a thick layer of peptidoglycan. The polyol phosphate subunits of these glycopolymers are decorated with GlcNAc sugars that are involved in phage binding, genetic exchange, host antibody response, resistance, and virulence. The search for the enzymes responsible for GlcNAcylation in Staphylococcus aureus has recently identified TarM and TarS with respective α-and β-(1-4) glycosyltransferase activities. The stereochemistry of the GlcNAc attachment is important in balancing biological processes, such that the interplay of TarM and TarS is likely important for bacterial pathogenicity and survival. Here we present the crystal structure of TarM in an unusual ternary-like complex consisting of a polymeric acceptor substrate analog, UDP from a hydrolyzed donor, and an α-glyceryl-GlcNAc product formed in situ. These structures support an internal nucleophilic substitution-like mechanism, lend new mechanistic insight into the glycosylation of glycopolymers, and reveal a trimerization domain with a likely role in acceptor substrate scaffolding.glycosyltransferase | wall teichoic acid | cell wall | crystal structure | bacterial pathogenicity

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Section: Discussionmentioning

confidence: 99%

Structure and mechanism ofStaphylococcus aureusTarM, the wall teichoic acid α-glycosyltransferase

Sobhanifar

Worrall

Gruninger

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…In addition, SRR glycoproteins may also mediate interactions between bacteria, facilitating biofilm formation and bacterial colonization (18). The SRR-containing adhesins are a major contributor to bacterial infections, including infective endocarditis, pneumococcal pneumonia, neonatal sepsis, and meningitis (19). In view of their roles in a broad spectrum of infections, these adhesins and their biogenesis machinery are major potential targets for novel antibacterial agents.…”

mentioning

confidence: 99%

Mechanism of a cytosolic O -glycosyltransferase essential for the synthesis of a bacterial adhesion protein

Chen

Seepersaud

Bensing

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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O-glycosylation of Ser and Thr residues is an important process in all organisms, which is only poorly understood. Such modification is required for the export and function of adhesin proteins that mediate the attachment of pathogenic Gram-positive bacteria to host cells. Here, we have analyzed the mechanism by which the cytosolic O-glycosyltransferase GtfA/B of Streptococcus gordonii modifies the Ser/Thr-rich repeats of adhesin. The enzyme is a tetramer containing two molecules each of GtfA and GtfB. The two subunits have the same fold, but only GtfA contains an active site, whereas GtfB provides the primary binding site for adhesin. During a first phase of glycosylation, the conformation of GtfB is restrained by GtfA to bind substrate with unmodified Ser/Thr residues. In a slow second phase, GtfB recognizes residues that are already modified with N-acetylglucosamine, likely by converting into a relaxed conformation in which one interface with GtfA is broken. These results explain how the glycosyltransferase modifies a progressively changing substrate molecule.

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“…Recently, a family of serine-rich (Srr) glycosylated proteins has been discovered in Streptococcus species and Staphylococcus aureus (32,33). Well-studied members include the fimbriae-associated adhesin Fap1 of Streptococcus parasanguinis (34), the human-platelet binding protein GspB of Streptococcus gordonii (35), the SraP and PsrP adhesins of Staphylococcus aureus and Streptococcus pneumoniae, respectively (36,37) and the Srr1 adhesin of S. agalactiae (36, 38 -42).…”

mentioning

confidence: 99%

O-Glycosylation of the N-terminal Region of the Serine-rich Adhesin Srr1 of Streptococcus agalactiae Explored by Mass Spectrometry

Chaze

Guillot

Valot³

et al. 2014

Molecular & Cellular Proteomics

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Serine-rich (Srr) proteins exposed at the surface of Gram-positive bacteria are a family of adhesins that contribute to the virulence of pathogenic staphylococci and streptococci. Lectin-binding experiments have previously shown that Srr proteins are heavily glycosylated. We report here the first mass-spectrometry analysis of the glycosylation of Streptococcus agalactiae Srr1. After Srr1 enrichment and trypsin digestion, potential glycopeptides were identified in collision induced dissociation spectra using X! Tandem. The approach was then refined using higher energy collisional dissociation fragmentation which led to the simultaneous loss of sugar residues, production of diagnostic oxonium ions and backbone fragmentation for glycopeptides. This Protein glycosylation takes place in bacteria. A considerable amount of information on the biochemical pathways involved in protein glycosylation has been obtained in the genera Campylobacter and Neisseria (1-3). Hence, functional studies performed on Gram-negative bacteria have revealed important properties of protein glycosylation pathways. Like in eukaryotes, proteins can be glycosylated on asparagines (N-glycosylation) or serine/threonine residues (O-glycosylation). Two modes of glycan transfer onto proteins have been characterized in Gram-negative bacteria. In the first, the activated glycan is synthesized on a lipid carrier on the cytoplasmic side of the membrane. After membrane translocation, the glycan portion of the polyprenyl-phosphate-glycan intermediate is transferred en bloc to the protein by an oligosaccharyltransferase active in the periplasm. Such mechanism has been demonstrated for N-glycosylation in Campylobacter jejuni (4 -6) and O-glycosylation in Neisseria gonorrheae (7-9). These pathways are responsible for the glycosylation of more than 65 proteins in C. jejuni (10) and 12 different proteins in N.

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A role for glycosylated serine‐rich repeat proteins in Gram‐positive bacterial pathogenesis

Cited by 90 publications

References 76 publications

Structure and mechanism ofStaphylococcus aureusTarM, the wall teichoic acid α-glycosyltransferase

Structure and mechanism ofStaphylococcus aureusTarM, the wall teichoic acid α-glycosyltransferase

Mechanism of a cytosolic O -glycosyltransferase essential for the synthesis of a bacterial adhesion protein

O-Glycosylation of the N-terminal Region of the Serine-rich Adhesin Srr1 of Streptococcus agalactiae Explored by Mass Spectrometry

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