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118  structures 34  species 2  interactions 216  sequences 5  architectures

Family: Peptidase_M27 (PF01742)

Summary: Clostridial neurotoxin zinc protease

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Clostridial neurotoxin zinc protease Provide feedback

These toxins are zinc proteases that block neurotransmitter release by proteolytic cleavage of synaptic proteins such as synaptobrevins, syntaxin and SNAP-25.

Literature references

  1. Montecucco C, Schiavo G, Tugnoli V, de Grandis D; , Mol Med Today 1996;2:418-424.: Botulinum neurotoxins: mechanism of action and therapeutic applications. PUBMED:8897436 EPMC:8897436

  2. Montecucco C, Schiavo G; , Trends Biochem Sci 1993;18:324-327.: Tetanus and botulism neurotoxins: a new group of zinc proteases. PUBMED:7901925 EPMC:7901925


Internal database links

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR000395

In the MEROPS database peptidases and peptidase homologues are grouped into clans and families. Clans are groups of families for which there is evidence of common ancestry based on a common structural fold:

  • Each clan is identified with two letters, the first representing the catalytic type of the families included in the clan (with the letter 'P' being used for a clan containing families of more than one of the catalytic types serine, threonine and cysteine). Some families cannot yet be assigned to clans, and when a formal assignment is required, such a family is described as belonging to clan A-, C-, M-, N-, S-, T- or U-, according to the catalytic type. Some clans are divided into subclans because there is evidence of a very ancient divergence within the clan, for example MA(E), the gluzincins, and MA(M), the metzincins.
  • Peptidase families are grouped by their catalytic type, the first character representing the catalytic type: A, aspartic; C, cysteine; G, glutamic acid; M, metallo; N, asparagine; S, serine; T, threonine; and U, unknown. The serine, threonine and cysteine peptidases utilise the amino acid as a nucleophile and form an acyl intermediate - these peptidases can also readily act as transferases. In the case of aspartic, glutamic and metallopeptidases, the nucleophile is an activated water molecule. In the case of the asparagine endopeptidases, the nucleophile is asparagine and all are self-processing endopeptidases.

In many instances the structural protein fold that characterises the clan or family may have lost its catalytic activity, yet retain its function in protein recognition and binding.

Metalloproteases are the most diverse of the four main types of protease, with more than 50 families identified to date. In these enzymes, a divalent cation, usually zinc, activates the water molecule. The metal ion is held in place by amino acid ligands, usually three in number. The known metal ligands are His, Glu, Asp or Lys and at least one other residue is required for catalysis, which may play an electrophillic role. Of the known metalloproteases, around half contain an HEXXH motif, which has been shown in crystallographic studies to form part of the metal-binding site [PUBMED:7674922]. The HEXXH motif is relatively common, but can be more stringently defined for metalloproteases as 'abXHEbbHbc', where 'a' is most often valine or threonine and forms part of the S1' subsite in thermolysin and neprilysin, 'b' is an uncharged residue, and 'c' a hydrophobic residue. Proline is never found in this site, possibly because it would break the helical structure adopted by this motif in metalloproteases [PUBMED:7674922].

This group of metallopeptidases belong to MEROPS peptidase family M27 (clan MA(E)). A number of the proteins have been classified as non-peptidase homologues as they have been found experimentally to be without peptidase activity, or lack amino acid residues that are believed to be essential for the catalytic activity of peptidases in the family.

There are seven antigenically distinct forms of botulinum neurotoxin, designated A, B, C1, D, E, F and G. The seven neurotoxins are potent protein toxins that inhibit neurotransmitter release from peripheral cholinergic synapses [PUBMED:2160960]. On binding to the neuronal synapses, the molecules are internalised and move by retrograde transport up the axon into the spinal cord, where they can move between post- and presynaptic neurons. The toxin inhibits neurotransmitter release by acting as a zinc endopeptidase that cleaves synaptic proteins such as synaptobrevins, syntaxin and SNAP-25 [PUBMED:8897436]. The protein toxins exist as disulphide-linked heterodimers of light and heavy chains. The light chain has the pharmacological activity, while the N- and C-termini of the heavy chain mediate channel formation and toxin binding [PUBMED:2160960]. The light chain exhibits a high level of sequence similarity to tetanus toxin (TeTx). Alignment of all characterised neurotoxin sequences reveals the presence of highly conserved amino acid domains interspersed with amino acid tracts with little overall similarity. The most divergent region corresponds to the C-terminal extremity of each toxin, which may reflect differences in specificity of binding to neurone acceptor sites [PUBMED:1541280].

Gene Ontology

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Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Alignments

We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the NCBI sequence database, and our metagenomics sequence database. More...

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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.

  Seed
(13)
Full
(216)
Representative proteomes NCBI
(238)
Meta
(0)
RP15
(2)
RP35
(5)
RP55
(5)
RP75
(5)
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available

Key: ✓ available, x not generated, not available.

Format an alignment

  Seed
(13)
Full
(216)
Representative proteomes NCBI
(238)
Meta
(0)
RP15
(2)
RP35
(5)
RP55
(5)
RP75
(5)
Alignment:
Format:
Order:
Sequence:
Gaps:
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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
(13)
Full
(216)
Representative proteomes NCBI
(238)
Meta
(0)
RP15
(2)
RP35
(5)
RP55
(5)
RP75
(5)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download    
Gzipped Download   Download   Download   Download   Download   Download   Download    

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_407 (release 4.2)
Previous IDs: none
Type: Family
Author: Bateman A
Number in seed: 13
Number in full: 216
Average length of the domain: 366.70 aa
Average identity of full alignment: 42 %
Average coverage of the sequence by the domain: 32.95 %

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 20.1 20.1
Trusted cut-off 20.4 20.6
Noise cut-off 19.2 20.0
Model length: 408
Family (HMM) version: 12
Download: download the raw HMM for this family

Species distribution

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Interactions

There are 2 interactions for this family. More...

Toxin_trans Peptidase_M27

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 Peptidase_M27 domain has been found. There are 118 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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