Summary

A-macroglobulin complement component

This family includes the complement components region of the alpha-2-macroglobulin family.

Literature references

Huang W, Dolmer K, Liao X, Gettins PG; , J Biol Chem 2000;275:1089-1094.: NMR solution structure of the receptor binding domain of human alpha(2)-macroglobulin. PUBMED:10625650
Xiao T, DeCamp DL, Spran SR; , Protein Sci 2000;9:1889-1897.: Structure of a rat alpha 1-macroglobulin receptor-binding domain dimer. PUBMED:11106161
Szakonyi G, Guthridge JM, Li D, Young K, Holers VM, Chen XS; , Science 2001;292:1725-1728.: Structure of complement receptor 2 in complex with its C3d ligand. PUBMED:11387479
Zanotti G, Bassetto A, Battistutta R, Folli C, Arcidiaco P, Stoppini M, Berni R; , Biochim Biophys Acta 2000;1478:232-238.: Structure at 1.44 A resolution of an N-terminally truncated form of the rat serum complement C3d fragment. PUBMED:10825534

InterPro entry IPR011626

This domain covers the complement component region of the alpha-2-macroglobulin family.

The alpha-macroglobulin (aM) family of proteins includes protease inhibitors PUBMED:2473064, typified by the human tetrameric a2-macroglobulin (a2M); they belong to the MEROPS proteinase inhibitor family I39, clan IL. These protease inhibitors share several defining properties, which include (i) the ability to inhibit proteases from all catalytic classes, (ii) the presence of a 'bait region' and a thiol ester, (iii) a similar protease inhibitory mechanism and (iv) the inactivation of the inhibitory capacity by reaction of the thiol ester with small primary amines. aM protease inhibitors inhibit by steric hindrance PUBMED:2472396. The mechanism involves protease cleavage of the bait region, a segment of the aM that is particularly susceptible to proteolytic cleavage, which initiates a conformational change such that the aM collapses about the protease. In the resulting aM-protease complex, the active site of the protease is sterically shielded, thus substantially decreasing access to protein substrates. Two additional events occur as a consequence of bait region cleavage, namely (i) the h-cysteinyl-g-glutamyl thiol ester becomes highly reactive and (ii) a major conformational change exposes a conserved COOH-terminal receptor binding domain PUBMED:2469470 (RBD). RBD exposure allows the aM protease complex to bind to clearance receptors and be removed from circulation PUBMED:2430968. Tetrameric, dimeric, and, more recently, monomeric aM protease inhibitors have been identified PUBMED:9914899, PUBMED:10426429.

Clan

This family is a member of clan 6_Hairpin (CL0059), which contains the following 20 members:

A2M_comp Bac_rhamnosid C5-epim_C DUF1680 DUF608 GDE_C GlcNAc_2-epim Glyco_hydro_15 Glyco_hydro_47 Glyco_hydro_48 Glyco_hydro_63 Glyco_hydro_65m Glyco_hydro_76 Glyco_hydro_8 Glyco_hydro_88 Glyco_hydro_9 Invertase_neut Pec_lyase Prenyltrans Trehalase

Gene Ontology

Cellular component

extracellular space (GO:0005615)

External database links

HOMSTRAD:	A2M_A A2M_B
PANDIT:	PF07678
PROSITE:	PDOC00440
SCOP:	1bv8
SYSTERS:	A2M_comp

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

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 (43) Full (741) NCBI (1219) Metagenomics (24)
Viewer:

Formatting options

Alignment:	Seed (43) Full (741)
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 (43) Full (741) NCBI (1219) Metagenomics (24)
Full length sequences	Full-sequences (741)

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 HMMER2.

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:

Prosite

Previous IDs:

A2M3;

Type:

Domain

Author:

Studholme DJ, Sammut SJ

Number in seed:

43

Number in full:

741

Average length of the domain:

208.20 aa

Average identity of full alignment:

32 %

Average coverage of the sequence by the domain:

19.28 %

HMM information

HMM build commands:

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

search method: hmmsearch -Z 9421015 -E 1000 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:

246

Family (HMM) version:

7

Download:

download the raw HMM for this family

Species distribution

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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Interactions

There are 5 interactions for this family. More...

Sushi A2M_recep A2M_N A2M_comp Thiol-ester_cl

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 MSD 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 A2M_comp domain has been found.

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Family: A2M_comp (PF07678)

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