Sialidase‐like Asp‐boxes: Sequence‐similar structures within different protein folds

Copley, Richard R.; Russell, Robert B.; Ponting, Chris P.

doi:10.1110/ps.31901

Cited by 70 publications

(74 citation statements)

References 46 publications

(51 reference statements)

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“…Following the signal peptide is a peptidoglycan-binding domain (30 to 180 aa). The C terminus (180 to 526 aa) is a conserved neuraminidase domain (12,13,84). Sequence alignment analysis further revealed that the C terminus of Sia Pg has a conserved catalytic domain of neuraminidase, which consists of one RIP motif and three Asp-box motifs ( (Fig.…”

Section: Resultsmentioning

confidence: 99%

Abrogation of Neuraminidase Reduces Biofilm Formation, Capsule Biosynthesis, and Virulence of Porphyromonas gingivalis

Kurniyati

Hu³

et al. 2012

Infect Immun

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The oral bacterium Porphyromonas gingivalis is a key etiological agent of human periodontitis, a prevalent chronic disease that affects up to 80% of the adult population worldwide. P. gingivalis exhibits neuraminidase activity. However, the enzyme responsible for this activity, its biochemical features, and its role in the physiology and virulence of P. gingivalis remain elusive. In this report, we found that P. gingivalis encodes a neuraminidase, PG0352 (Sia Pg ). Transcriptional analysis showed that PG0352 is monocistronic and is regulated by a sigma 70 -like promoter. Biochemical analyses demonstrated that Sia Pg is an exo-␣-neuraminidase that cleaves glycosidic-linked sialic acids. Cryoelectron microscopy and tomography analyses revealed that the PG0352 deletion mutant (⌬PG352) failed to produce an intact capsule layer. Compared to the wild type, in vitro studies showed that ⌬PG352 formed less biofilm and was less resistant to killing by the host complement. In vivo studies showed that while the wild type caused a spreading type of infection that affected multiple organs and all infected mice were killed, ⌬PG352 only caused localized infection and all animals survived. Taken together, these results demonstrate that Sia Pg is an important virulence factor that contributes to the biofilm formation, capsule biosynthesis, and pathogenicity of P. gingivalis, and it can potentially serve as a new target for developing therapeutic agents against P. gingivalis infection.

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Section: Resultsmentioning

confidence: 99%

Abrogation of Neuraminidase Reduces Biofilm Formation, Capsule Biosynthesis, and Virulence of Porphyromonas gingivalis

Kurniyati

Hu³

et al. 2012

Infect Immun

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“…The incomplete sialidase domain contains one aspartic acid box motif. This motif, common among sialidases (12), is found three times in NanH. It is suspected that the unsequenced 5Ј end of the M. haemolytica neuraminidase gene encodes two additional aspartic acid boxes orthologous to those of NanH.…”

Section: Resultsmentioning

confidence: 99%

The Genome Sequence of Mannheimia haemolytica A1: Insights into Virulence, Natural Competence, and Pasteurellaceae Phylogeny

Gioia¹,

Qin

Jiang

et al. 2006

J Bacteriol

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The draft genome sequence of Mannheimia haemolytica A1, the causative agent of bovine respiratory disease complex (BRDC), is presented. Strain ATCC BAA-410, isolated from the lung of a calf with BRDC, was the DNA source. The annotated genome includes 2,839 coding sequences, 1,966 of which were assigned a function and 436 of which are unique to M. haemolytica. Through genome annotation many features of interest were identified, including bacteriophages and genes related to virulence, natural competence, and transcriptional regulation. In addition to previously described virulence factors, M. haemolytica encodes adhesins, including the filamentous hemagglutinin FhaB and two trimeric autotransporter adhesins. Two dual-function immunoglobulin-protease/adhesins are also present, as is a third immunoglobulin protease. Genes related to iron acquisition and drug resistance were identified and are likely important for survival in the host and virulence. Analysis of the genome indicates that M. haemolytica is naturally competent, as genes for natural competence and DNA uptake signal sequences (USS) are present. Comparison of competence loci and USS in other species in the family Pasteurellaceae indicates that M. haemolytica, Actinobacillus pleuropneumoniae, and Haemophilus ducreyi form a lineage distinct from other Pasteurellaceae. This observation was supported by a phylogenetic analysis using sequences of predicted housekeeping genes.Mannheimia haemolytica serotype A1 is the principle bacterial pathogen associated with bovine respiratory disease complex, also known as bovine shipping fever (25, 31). M. haemolytica resides in the upper respiratory tracts of healthy ruminants, although in immunocompromised animals, such as those with a preexisting viral infection, M. haemolytica can descend into the lungs, leading to pneumonia. The mortality and morbidity associated with this disease cause substantial losses to the cattle industry (25, 31). Hence, much research on M. haemolytica is directed at understanding its virulence and designing vaccines to protect cattle (31).M. haemolytica is a member of the family Pasteurellaceae, which is classified among the ␥-proteobacteria and includes human and animal pathogens of the genera Mannheimia, Pasteurella, Haemophilus, Actinobacillus, and Histophilus (31). M. haemolytica (formerly Pasteurella haemolytica) is classified in the genus Mannheimia based upon 16S rRNA sequence phylogeny and DNA-DNA hybridizations (3). The family Pasteurellaceae includes several members whose genomes have been sequenced: Haemophilus influenzae, Pasteurella multocida, Mannheimia succiniciproducens, Actinobacillus pleuropneumoniae, Histophilus somni, Haemophilus ducreyi, and Actinobacillus actinomycetemcomitans.The primary virulence factor of M. haemolytica is considered the leukotoxin. It is a calcium-dependent toxin that is a member of the RTX family of toxins. Cytolytic at low concentrations and apoptotic at high concentrations, the leukotoxin provokes an inflammatory response that can lead to intense ed...

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“…It encodes Reelin (a gigantic secreted protein of 3,460 amino acids), which consists of an N-terminal signal peptide, an F-spondin-like domain, a unique region, and eight tandem repeats of 350-390 residues termed ''Reelin repeats'' (Figure 2A). 18,19 Each Reelin repeat comprises a central epidermal growth factor (EGF) or EGFlike module flanked by two subrepeats (A and B), each containing a 14-amino-acid Asp-box (bacterial neuraminidase repeat) motif 20 (Figures 2A and 2B). Both the EGF-like and Asp-box modules support the compact, ''horseshoe-like'' structural arrangement of each Reelin repeat 21 (Figure 3).…”

mentioning

confidence: 99%

“…Two amino acid substitutions, p.His798Asn and p.Gly2783Cys, affect residues in Asp-boxes 2 and 13, respectively ( Figures 2B and 2C), most likely resulting in structural abnormalities. Particularly, the p.Gly2783Cys substitution replaces an invariant Gly residue at position 8 in the Asp-box consensus sequence 20 with a cysteine (Figure 2C), most likely altering the conformation of Aspbox 13. To evaluate the potential impact of the ADLTErelated amino acid substitutions on the structure of Reelin repeats, we generated a 3D model of the three Reelin repeats harboring these amino acid changes.…”

mentioning

confidence: 99%

Heterozygous Reelin Mutations Cause Autosomal-Dominant Lateral Temporal Epilepsy

Dazzo

Fanciulli²,

Serioli

et al. 2015

The American Journal of Human Genetics

106

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Autosomal-dominant lateral temporal epilepsy (ADLTE) is a genetic epilepsy syndrome clinically characterized by focal seizures with prominent auditory symptoms. ADLTE is genetically heterogeneous, and mutations in LGI1 account for fewer than 50% of affected families. Here, we report the identification of causal mutations in reelin (RELN) in seven ADLTE-affected families without LGI1 mutations. We initially investigated 13 ADLTE-affected families by performing SNP-array linkage analysis and whole-exome sequencing and identified three heterozygous missense mutations co-segregating with the syndrome. Subsequent analysis of 15 small ADLTE-affected families revealed four additional missense mutations. 3D modeling predicted that all mutations have structural effects on protein-domain folding. Overall, RELN mutations occurred in 7/40 (17.5%) ADLTE-affected families. RELN encodes a secreted protein, Reelin, which has important functions in both the developing and adult brain and is also found in the blood serum. We show that ADLTE-related mutations significantly decrease serum levels of Reelin, suggesting an inhibitory effect of mutations on protein secretion. We also show that Reelin and LGI1 co-localize in a subset of rat brain neurons, supporting an involvement of both proteins in a common molecular pathway underlying ADLTE. Homozygous RELN mutations are known to cause lissencephaly with cerebellar hypoplasia. Our findings extend the spectrum of neurological disorders associated with RELN mutations and establish a link between RELN and LGI1, which play key regulatory roles in both the developing and adult brain.Temporal-lobe epilepsy is the most common type of focal epilepsy. It is sometimes associated with structural brain lesions, but genetic forms have also been described. Familial temporal-lobe epilepsy comprises two genetically distinct syndromes: familial mesial temporal-lobe epilepsy (FMTLE [MIM: 611630]) 1 and autosomal-dominant lateral temporal epilepsy (ADLTE [MIM: 600512]), also named autosomal-dominant partial epilepsy with auditory features (ADPEAF). 2 ADLTE is a well-defined epileptic syndrome clinically characterized by focal seizures with prominent auditory and/or aphasic symptoms, normal brain MRI, and relatively benign evolution. 2,3 Its inheritance pattern is autosomal dominant with reduced penetrance (around 70%). Mutations associated with ADLTE are found in leucine-rich, glioma inactivated 1 (LGI1 [MIM: 604619]) 4-6 in 30%-50% of ADLTE-affected families. 3,7,8 Other genes harboring ADLTE-causing mutations are unknown.LGI1 is expressed mainly in neurons, particularly in the neocortex and limbic regions, 4,9 and its protein product, LGI1, is secreted. 9 LGI1 has been implicated in the transmission of K þ and AMPA synaptic currents 10,11 and in the regulation of post-natal maturation of cortical excitatory synapses and dendrite pruning. 12 However, it is not known which of these functions underlies ADLTE. Identification of additional genes whose mutations cause ADLTE will help to clarify the pathoge...

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Sialidase‐like Asp‐boxes: Sequence‐similar structures within different protein folds

Cited by 70 publications

References 46 publications

Abrogation of Neuraminidase Reduces Biofilm Formation, Capsule Biosynthesis, and Virulence of Porphyromonas gingivalis

Abrogation of Neuraminidase Reduces Biofilm Formation, Capsule Biosynthesis, and Virulence of Porphyromonas gingivalis

The Genome Sequence of Mannheimia haemolytica A1: Insights into Virulence, Natural Competence, and Pasteurellaceae Phylogeny

Heterozygous Reelin Mutations Cause Autosomal-Dominant Lateral Temporal Epilepsy

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