The Cysteine-rich Protein A from Helicobacter pyloriIs a β-Lactamase

Mittl, Peer R. E.; Lüthy, Lucas; Hunziker, Peter; Grütter, Markus G.

doi:10.1074/jbc.m001869200

Cited by 37 publications

(49 citation statements)

References 34 publications

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“…pylori HcpA protein belongs to a group of unique and highly disulfide-bridged proteins (8). Mittl and coworkers have recently reported HcpA to possess weak ␤-lactamase activity and speculated on a role of HcpA in maintenance of cell wall proteoglycan through the bacterial cell cycle (31,34). However, the described weak enzymatic activity does not exclude in vivo immunomodulatory properties of secreted HcpA.…”

Section: Vol 73 2005mentioning

confidence: 98%

“…In HcpA six pairs of cysteine residues, which are separated by exactly seven amino acid residues, form disulfide bridges (34). Although no in vivo function has been assigned to members of the Hcp family thus far, it could be demonstrated that HcpA (HP0211), HcpB (HP0336), and HcpD (HP0160) possess weak penicillin-binding activities (31,34). In a comprehensive immunoproteomics study, increased HcpC antibody titers were detected in sera of patients with gastric adenocarcinoma (20).…”

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confidence: 96%

“…In addition, very recently, a novel putative member of the Hcp family has been identified by our group within the genome of Wolinella succinogenes, termed WcpA (NCBI accession number BX571656). In HcpA six pairs of cysteine residues, which are separated by exactly seven amino acid residues, form disulfide bridges (34). Although no in vivo function has been assigned to members of the Hcp family thus far, it could be demonstrated that HcpA (HP0211), HcpB (HP0336), and HcpD (HP0160) possess weak penicillin-binding activities (31,34).…”

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confidence: 99%

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Characterization of theHelicobacter pyloriCysteine-Rich Protein A as a T-Helper Cell Type 1 Polarizing Agent

et al. 2005

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Section: Vol 73 2005mentioning

confidence: 98%

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confidence: 96%

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Characterization of theHelicobacter pyloriCysteine-Rich Protein A as a T-Helper Cell Type 1 Polarizing Agent

et al. 2005

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“…The proteins bearing this repeat are typically built of several consecutive a/a motifs, the antiparallel a-helices of the motifs being connected by a short loop [26]. Five of the nine members of this ''SLR'' (for Sel1-like repeat) protein family are rich in cysteine residues and had been designated as ''Helicobacter cysteine rich proteins'' (Hcp) [27,28]; The ahelices of each SLR repeat are bridged by a disulfide bond, which is a unique feature of Hcps [26]. Although the in vivo function of H. pylori SLR proteins is not known, some Hcps bind b-lactam compounds [27,29], which suggests possible interactions with immunomodulatory peptidoglycan fragments, that could affect the innate immune response [30].…”

Section: Introductionmentioning

confidence: 99%

“…Five of the nine members of this ''SLR'' (for Sel1-like repeat) protein family are rich in cysteine residues and had been designated as ''Helicobacter cysteine rich proteins'' (Hcp) [27,28]; The ahelices of each SLR repeat are bridged by a disulfide bond, which is a unique feature of Hcps [26]. Although the in vivo function of H. pylori SLR proteins is not known, some Hcps bind b-lactam compounds [27,29], which suggests possible interactions with immunomodulatory peptidoglycan fragments, that could affect the innate immune response [30]. High antibody titres against four SLR proteins [Hp0211 (HcpA), Hp0235 (HcpE), Hp0336 (HcpB), and Hp1098 (HcpC)] were found in H. pylori-infected people [28], indicating in vivo expression and immune recognition.…”

Section: Introductionmentioning

confidence: 99%

Helicobacter pylori Evolution: Lineage-Specific Adaptations in Homologs of Eukaryotic Sel1-Like Genes

et al. 2005

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Geographic partitioning is postulated to foster divergence of Helicobacter pylori populations as an adaptive response to local differences in predominant host physiology. H. pylori's ability to establish persistent infection despite host inflammatory responses likely involves active management of host defenses using bacterial proteins that may themselves be targets for adaptive evolution. Sequenced H. pylori genomes encode a family of eight or nine secreted proteins containing repeat motifs that are characteristic of the eukaryotic Sel1 regulatory protein, whereas the related Campylobacter and Wolinella genomes each contain only one or two such ''Sel1-like repeat'' (SLR) genes (''slr genes''). Signatures of positive selection (ratio of nonsynonymous to synonymous mutations, d N /d S ¼ x . 1) were evident in the evolutionary history of H. pylori slr gene family expansion. Sequence analysis of six of these slr genes (hp0160, hp0211, hp0235, hp0519, hp0628, and hp1117) from representative East Asian, European, and African H. pylori strains revealed that all but hp0628 had undergone positive selection, with different amino acids often selected in different regions. Most striking was a divergence of Japanese and Korean alleles of hp0519, with Japanese alleles having undergone particularly strong positive selection (x J . 25), whereas alleles of other genes from these populations were intermingled. Homology-based structural modeling localized most residues under positive selection to SLR protein surfaces. Rapid evolution of certain slr genes in specific H. pylori lineages suggests a model of adaptive change driven by selection for fine-tuning of host responses, and facilitated by geographic isolation. Characterization of such local adaptations should help elucidate how H. pylori manages persistent infection, and potentially lead to interventions tailored to diverse human populations.

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Structural characterization of the Sel1‐like repeat protein LceB from Legionella pneumophila

Penner,

Lorente Cobo,

Patel

et al. 2024

Protein Science

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Legionella are freshwater Gram‐negative bacteria that in their normal environment infect protozoa. However, this adaptation also allows Legionella to infect human alveolar macrophages and cause pneumonia. Central to Legionella pathogenesis are more than 330 secreted effectors, of which there are 9 core effectors that are conserved in all pathogenic species. Despite their importance, the biochemical function of several core effectors remains unclear. To address this, we have taken a structural approach to characterize the core effector of unknown function LceB, or Lpg1356, from Legionella pneumophila. Here we solve an X‐ray crystal structure of LceB using an AlphaFold model for molecular replacement. The experimental structure shows that LceB adopts a Sel1‐like repeat fold as predicted. However, the crystal structure captured multiple conformations of LceB all of which differed from the AlphaFold model. Comparison of the predicted model and the experimental models suggests that LceB is highly flexible in solution. Additionally, molecular analysis of LceB using its close structural homologues reveals sequence and structural motifs of known biochemical function. Specifically, LceB harbors a repeated KAAEQG motif that both stabilizes the Sel1‐like repeat fold and is known to participate in protein‐protein interactions with eukaryotic host proteins. We also observe that LceB forms several higher‐order oligomers in solution. Overall, our results have revealed that LceB has conformational flexibility, self‐associates, and contains a molecular surface for binding a target host‐cell protein. Additionally, our data provides structural insights into the Sel1‐like repeat family of proteins that remain poorly studied.This article is protected by copyright. All rights reserved.

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The Cysteine-rich Protein A from Helicobacter pyloriIs a β-Lactamase

Cited by 37 publications

References 34 publications

Characterization of theHelicobacter pyloriCysteine-Rich Protein A as a T-Helper Cell Type 1 Polarizing Agent

Characterization of theHelicobacter pyloriCysteine-Rich Protein A as a T-Helper Cell Type 1 Polarizing Agent

Helicobacter pylori Evolution: Lineage-Specific Adaptations in Homologs of Eukaryotic Sel1-Like Genes

Structural characterization of the Sel1‐like repeat protein LceB from Legionella pneumophila

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