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1  structure 43  species 0  interactions 1164  sequences 6  architectures

Family: VacA (PF02691)

Summary: Vacuolating cyotoxin

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Vacuolating cyotoxin Provide feedback

This family consists of Vacuolating cyotoxin proteins form Proteobacteria. These proteins are an important virulence determinate in H. pylori and induce cytoplasmic vacuolation in a variety of mammalian cell lines [1].

Literature references

  1. Atherton JC, Cao P, Peek RM Jr, Tummuru MK, Blaser MJ, Cover TL; , J Biol Chem 1995;270:17771-17777.: Mosaicism in vacuolating cytotoxin alleles of Helicobacter pylori. Association of specific vacA types with cytotoxin production and peptic ulceration. PUBMED:7629077 EPMC:7629077


External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR003842

Helicobacter pylori is a micro-aerophilic bacterium with the extraordinary ability to establish infections in human stomachs that can last for years or decades, despite immune and inflammatory responses and normal turnover of the gastric epithelium and overlying mucin layer in which it resides. Most H. pylori strains secrete a toxin (VacA) that induces multiple structural and functional alterations in eukaryotic cells. The most prominent effect of VacA is its capacity to induce the formation of large cytoplasmic vacuoles in eukaryotic cells. In addition, VacA interferes with the process of antigen presentation, increases permeability of polarised epithelial cell monolayers, and forms anion-selective membrane channels. Formation of channels in endosomal membranes of cells may be an important feature of the mechanism by which VacA induces cell vacuolation. H. pylori vacA encodes a ~139kDa protoxin, which undergoes cleavage of a 33-residue N-terminal signal sequence and C-terminal proteolytic processing to yield a mature secreted toxin. Purified VacA degrades during prolonged storage into two fragments (of ~34 and 58kDa), which are derived from the N- and the C terminus of the toxin respectively. The mass of the experimentally intact toxin (~88.2kDa) corresponds closely to the sum of the masses of the two proteolytic fragments [PUBMED:11160018].

Secondary structure predictions suggest that a 35kDa portion of the VacA C-terminal domain is rich in amphipathic beta-sheets, and this region exhibits low-level similarity to members of the family of autotransporter proteins. In addition, at the C terminus of VacA, there is a phenylalanine- containing motif that is commonly found in autotransporter proteins, as well as in numerous Gram-negative bacterial outer membrane proteins. An intact N-terminal portion of VacA is not required for proteolytic processing of the protoxin. However, the N-terminal 32 amino acids of the mature VacA are predicted to form the only contiguous hydrophobic region in the protein that is long enough to span the membrane. What is more, isogenic H. pylori mutant strains in which the C-terminal VacA domain is disrupted, fail to express or secrete any detectable VacA, which is probably attributable to the degradation of export-incompetent toxin precursors within the periplasm. It is speculated that the VacA protoxin may undergo proteolytic cleavage at multiple sites downstream from amino acid 854 of the protoxin, which would yield a 33kDa cell-associated domain, as well as a fragment of ~15kDa [PUBMED:11160018].

Gene Ontology

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Domain organisation

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Alignments

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We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

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(1164)
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(1174)
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RP35
(2)
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  Seed
(2)
Full
(1164)
Representative proteomes NCBI
(1174)
Meta
(1)
RP15
(1)
RP35
(2)
RP55
(2)
RP75
(2)
Alignment:
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We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.

  Seed
(2)
Full
(1164)
Representative proteomes NCBI
(1174)
Meta
(1)
RP15
(1)
RP35
(2)
RP55
(2)
RP75
(2)
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You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.

Pfam alignments:

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...

Trees

This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

Note: You can also download the data file for the tree.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Pfam-B_436 (release 5.5)
Previous IDs: none
Type: Family
Author: Bashton M, Bateman A
Number in seed: 2
Number in full: 1164
Average length of the domain: 244.10 aa
Average identity of full alignment: 38 %
Average coverage of the sequence by the domain: 85.28 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 18.9 18.9
Trusted cut-off 19.3 19.1
Noise cut-off 17.7 17.7
Model length: 981
Family (HMM) version: 10
Download: download the raw HMM for this family

Species distribution

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Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the VacA domain has been found. There are 1 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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