Summary: Astacin (Peptidase family M12A)

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Wikipedia: Astacin
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Astacin

structure of astacin with a hydroxamic acid inhibitor

Identifiers

Symbol

Astacin

Pfam clan

Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe
PDBsum	structure summary

astacin

Identifiers

Databases

PDB structures

AmiGO / EGO

Search
PMC	articles
PubMed	articles

In molecular biology, astacin is a family of metallopeptidases. These metallopeptidases belong to the MEROPS peptidase family M12, subfamily M12A (astacin family, clan MA(M)). The protein fold of the peptidase domain for members of this family resembles that of thermolysin, the type example for clan MA and the predicted active site residues for members of this family and thermolysin occur in the motif HEXXH.^[1]

The astacin family of metalloendopeptidases (EC 3.4.24.21) encompasses a range of proteins found in hydra to humans, in mature and developmental systems.^[2] Their functions include activation of growth factors, degradation of polypeptides, and processing of extracellular proteins.^[2] The proteins are synthesised with N-terminal signal and pro-enzyme sequences, and many contain multiple domains C-terminal to the protease domain. They are either secreted from cells, or are associated with the plasma membrane.

The astacin molecule adopts a kidney shape, with a deep active-site cleft between its N- and C-terminal domains.^[3] The zinc ion, which lies at the bottom of the cleft, exhibits a unique penta-coordinated mode of binding, involving 3 histidine residues, a tyrosine and a water molecule (which is also bound to the carboxylate side chain of Glu93).^[3] The N-terminal domain comprises 2 alpha-helices and a 5-stranded beta-sheet. The overall topology of this domain is shared by the archetypal zinc-endopeptidase thermolysin. Astacin protease domains also share common features with serralysins, matrix metalloendopeptidases, and snake venom proteases; they cleave peptide bonds in polypeptides such as insulin B chain and bradykinin, and in proteins such as casein and gelatin; and they have arylamidase activity.^[2]

[edit] Examples

Human genes encoding proteins containing the astacin domain include:

ASTL; BMP1; MEP1A; MEP1B; TLL1; TLL2

[edit] References

^ Rawlings ND, Barrett AJ (1995). "Evolutionary families of metallopeptidases". Meth. Enzymol. 248: 183–228. doi:10.1016/0076-6879(95)48015-3. PMID 7674922.
^ ^a ^b ^c Bond JS, Beynon RJ (July 1995). "The astacin family of metalloendopeptidases". Protein Sci. 4 (7): 1247–61. doi:10.1002/pro.5560040701. PMC 2143163. PMID 7670368. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2143163.
^ ^a ^b Gomis-Ruth FX, Stocker W, Huber R, Zwilling R, Bode W (February 1993). "Refined 1.8 A X-ray crystal structure of astacin, a zinc-endopeptidase from the crayfish Astacus astacus L. Structure determination, refinement, molecular structure and comparison with thermolysin". J. Mol. Biol. 229 (4): 945–68. doi:10.1006/jmbi.1993.1098. PMID 8445658.

[edit] External links

MEROPS family M12

This article incorporates text from the public domain Pfam and InterPro IPR001506

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

Astacin (Peptidase family M12A)

The members of this family are enzymes that cleave peptides. These proteases require zinc for catalysis. Members of this family contain two conserved disulphide bridges, these are joined 1-4 and 2-3. Members of this family have an amino terminal propeptide which is cleaved to give the active protease domain. All other linked domains are found to the carboxyl terminus of this domain. This family includes: Astacin P07584 a digestive enzyme from Crayfish. Meprin, Q16819 a multiple domain membrane component that is constructed from a homologous alpha and beta chain. Proteins involved in morphogenesis such as P13497 and Tolloid from drosophila P25723.

Literature references

Rawlings ND, Barrett AJ; , Meth Enzymol 1995;248:183-228.: Evolutionary families of metallopeptidases. PUBMED:7674922

Clan

This family is a member of clan Peptidase_MA (CL0126), which has a total of 52 members.

Internal database links

Similarity to PfamA using HHSearch:

Peptidase_M10 Peptidase_M57

External database links

HOMSTRAD:	Astacin
MEROPS:	M12
PANDIT:	PF01400
PROSITE:	PDOC00129
Pseudofam:	PF01400
SCOP:	1ast
SYSTERS:	Astacin

This tab holds annotation information from the InterPro database.

InterPro entry IPR001506

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 the MEROPS peptidase family M12, subfamily M12A (astacin family, clan MA(M)). The protein fold of the peptidase domain for members of this family resembles that of thermolysin, the type example for clan MA and the predicted active site residues for members of this family and thermolysin occur in the motif HEXXH [PUBMED:7674922].

The astacin (EC) family of metalloendopeptidases encompasses a range of proteins found in hydra to humans, in mature and developmental systems [PUBMED:7670368]. Their functions include activation of growth factors, degradation of polypeptides, and processing of extracellular proteins [PUBMED:7670368]. The proteins are synthesised with N-terminal signal and pro-enzyme sequences, and many contain multiple domains C-terminal to the protease domain. They are either secreted from cells, or are associated with the plasma membrane.

The astacin molecule adopts a kidney shape, with a deep active-site cleft between its N- and C-terminal domains [PUBMED:8445658]. The zinc ion, which lies at the bottom of the cleft, exhibits a unique penta-coordinated mode of binding, involving 3 histidine residues, a tyrosine and a water molecule (which is also bound to the carboxylate side chain of Glu93) [PUBMED:8445658]. The N-terminal domain comprises 2 alpha-helices and a 5-stranded beta-sheet. The overall topology of this domain is shared by the archetypal zinc-endopeptidase thermolysin. Astacin protease domains also share common features with serralysins, matrix metalloendopeptidases, and snake venom proteases; they cleave peptide bonds in polypeptides such as insulin B chain and bradykinin, and in proteins such as casein and gelatin; and they have arylamidase activity [PUBMED:7670368].

Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

Molecular function	metalloendopeptidase activity (GO:0004222)
Biological process	proteolysis (GO:0006508)

Domain organisation

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

Loading domain graphics...

Pfam Clan

This family is a member of clan Peptidase_MA (CL0126), which contains the following 52 members:

Astacin BSP DUF1570 DUF2201_N DUF2268 DUF3152 DUF3633 DUF3810 DUF4157 DUF45 DUF955 Enhancin HRXXH M60-like Peptidase_M1 Peptidase_M10 Peptidase_M11 Peptidase_M13 Peptidase_M2 Peptidase_M27 Peptidase_M3 Peptidase_M30 Peptidase_M32 Peptidase_M35 Peptidase_M36 Peptidase_M4 Peptidase_M41 Peptidase_M43 Peptidase_M48 Peptidase_M4_C Peptidase_M50 Peptidase_M50B Peptidase_M54 Peptidase_M56 Peptidase_M57 Peptidase_M6 Peptidase_M61 Peptidase_M64 Peptidase_M66 Peptidase_M7 Peptidase_M8 Peptidase_M84 Peptidase_M9 Peptidase_MA_2 Peptidase_U49 Reprolysin Reprolysin_2 Reprolysin_3 Reprolysin_4 SprT-like WLM Zn_peptidase

Alignments

There are various ways to view or download the sequence alignments that we store. You can use a sequence viewer to look at either the seed or full alignment for the family, or you can look at a plain text version of the sequence in a variety of different formats. More...

View options

Alignment:	Seed (26) Full (1294) NCBI (1707) Metagenomics (24)
Viewer:

Formatting options

Alignment:	Seed (26) Full (1294)
Format:
Order:	Tree Alphabetical
Sequence:	Inserts lower case All upper case
Gaps:
Download/view:	Download View

Download options

Very large alignments can often cause problems for the formatting tool above. If you find that downloading or viewing a large alignment is problematic, you can also download a gzip-compressed, Stockholm-format file containing the seed or full alignment for this family.

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

The main seed and full alignments are generated using sequences from the UniProt sequence database. However, we also generate alignments using sequences from the NCBI sequence database and the "metaseq" metagenomics dataset.

You can view alignments from these two additional datasets using the form above, or you can download alignments of NCBI or metagenomics sequences, as gzip-compressed files.

Pfam alignments:	Seed (26) Full (1294) NCBI (1707) Metagenomics (24)
Full length sequences	Full-sequences (1294)

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.

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. 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 or full alignments.

Note: You can also download the data files for the seed, full, NCBI or metagenomics trees.

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

Seed source:

Swissprot

Previous IDs:

none

Type:

Domain

Author:

Bateman A

Number in seed:

26

Number in full:

1294

Average length of the domain:

173.30 aa

Average identity of full alignment:

32 %

Average coverage of the sequence by the domain:

39.49 %

HMM information

HMM build commands:

build method: hmmbuild -o /dev/null HMM SEED

search method: hmmsearch -Z 15929002 -E 1000 --cpu 4 HMM pfamseq

Model details:

Parameter	Sequence	Domain
Gathering cut-off	20.5	20.5
Trusted cut-off	20.5	20.5
Noise cut-off	20.4	20.4

Model length:

191

Family (HMM) version:

19

Download:

download the raw HMM for this family

Species distribution

Sunburst
Tree

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number of species

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Colour assignments

Archea	Eukaryota
Bacteria	Other sequences
Viruses	Unclassified
Viroids	Unclassified sequence

This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab if you need to select sub-trees and view sequence alignments. More...

This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.

How the sunburst is generated

The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, it's distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.

In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:

superkingdom
kingdom
phylum
class
order
family
genus
species

Colouring and labels

Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.

As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.

Anomalies in the taxonomy tree

There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.

Missing taxonomic levels

Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.

Unmapped species names

The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.

So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".

Sub-species

Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.

Too many species/sequences

For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.

Tree controls

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The tree shows the occurrence of this domain across different species. More...

Species trees

We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.

Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.

If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.

Interactive tree

For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.

We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.

Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.

We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.

You can use the tree controls to manipulate how the interactive tree is displayed:

show/hide the summary boxes
highlight species that are represented in the seed alignment
expand/collapse the tree or expand it to a given depth
select a sub-tree or a set of species within the tree and view them graphically or as an alignment
save a plain text representation of the tree

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Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.

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 Astacin domain has been found. There are 4 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.

Loading structure mapping...

Family: Astacin (PF01400)

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Summary: Astacin (Peptidase family M12A)

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Astacin

[edit] Examples

[edit] References

[edit] External links

Astacin (Peptidase family M12A)

Literature references

Clan

Internal database links

External database links

InterPro entry IPR001506

Gene Ontology

Domain organisation

Pfam Clan

Alignments

Viewing

Downloading

View options

Formatting options

Download options

External links

HMM logo

Trees

Curation and family details

Curation

HMM information

Species distribution

Sunburst controls

Weight segments by...

Change the size of the sunburst

Colour assignments

How the sunburst is generated

Colouring and labels

Anomalies in the taxonomy tree

Missing taxonomic levels

Unmapped species names

Sub-species

Too many species/sequences

Tree controls

Annotation

Download tree

Selected sequences

Species trees

Interactive tree

Structures