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18  structures 133  species 0  interactions 416  sequences 6  architectures

Family: TIMP (PF00965)

Summary: Tissue inhibitor of metalloproteinase

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Tissue inhibitor of metalloproteinase Provide feedback

Members of this family are common in extracellular regions of vertebrate species

Literature references

  1. Williamson RA, Martorell G, Carr MD, Murphy G, Docherty AJ, Freedman RB, Feeney J; , Biochemistry 1994;33:11745-11759.: Solution structure of the active domain of tissue inhibitor of metalloproteinases-2. A new member of the OB fold protein family. PUBMED:7918391 EPMC:7918391


Internal database links

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR001820

Peptide proteinase inhibitors can be found as single domain proteins or as single or multiple domains within proteins; these are referred to as either simple or compound inhibitors, respectively. In many cases they are synthesised as part of a larger precursor protein, either as a prepropeptide or as an N-terminal domain associated with an inactive peptidase or zymogen. This domain prevents access of the substrate to the active site. Removal of the N-terminal inhibitor domain either by interaction with a second peptidase or by autocatalytic cleavage activates the zymogen. Other inhibitors interact direct with proteinases using a simple noncovalent lock and key mechanism; while yet others use a conformational change-based trapping mechanism that depends on their structural and thermodynamic properties.

Tissue inhibitors of metalloproteinases (TIMPs, [PUBMED:2793861, PUBMED:1850705, PUBMED:1512267]) and their target matrix metalloproteinases (MMPs, MEROPS peptidase family M10A) are important in connective tissue re-modelling in diseases of the cardiovascular system and in the physiological degradation of connective tissue, as well as in pathological states such as tumour invasion and arthritis. TIMPs belong to MEROPS proteinase inhibitor family I35, clan IT.

TIMPs complex with extracellular matrix metalloproteinases (such as collagenases) and irreversibly inactivate them. Members of this family are common in extracellular regions of vertebrate species [PUBMED:7918391]. TIMPs are proteins of about 200 amino acid residues, 12 of which are cysteines involved in disulphide bonds [PUBMED:2163605]. The basic structure of such a type of inhibitor is shown in the following schematic representation:

          +-----------------------------+         +--------------+
          |                             |         |              |
        CxCxCxxxxxxxxxxxxxxxxxCxxxxxxxxxCxxxxxxxCxCxCxCxCxxxxxCxxCxxx
        |   |                 |                 |   | | |     |
        |   +-----------------|-----------------+   +-+ +-----+
        +---------------------+
'C': conserved cysteine involved in a disulphide bond.

The crystal structure of the human proMMP-2/TIMP-2 complex reveals an interaction between the hemopexin domain of proMMP-2 and the C-terminal domain of TIMP-2, leaving the catalytic site of MMP-2 and the inhibitory site of TIMP-2 distant and spatially isolated. The interfacial contact of these two proteins is characterised by two distinct binding regions composed of alternating hydrophobic and hydrophilic interactions. This unique structure provides information for how specificity for non-inhibitory MMP/TIMP complex formation is achieved [PUBMED:12032297].

Gene Ontology

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

Domain organisation

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

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Pfam Clan

This family is a member of clan TIMP-like (CL0353), which has the following description:

This superfamily consists of the C-terminal domains of netrins, complement proteins C3, C4, C5, secreted frizzled-related proteins, and type I procollagen C-proteinase enhancer proteins, as well as the homologous N-terminal domains of tissue inhibitors of metalloproteinases (TIMPs).

The clan contains the following 2 members:

NTR TIMP

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
(25)
Full
(416)
Representative proteomes NCBI
(403)
Meta
(1)
RP15
(51)
RP35
(65)
RP55
(110)
RP75
(187)
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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
(25)
Full
(416)
Representative proteomes NCBI
(403)
Meta
(1)
RP15
(51)
RP35
(65)
RP55
(110)
RP75
(187)
Alignment:
Format:
Order:
Sequence:
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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
(25)
Full
(416)
Representative proteomes NCBI
(403)
Meta
(1)
RP15
(51)
RP35
(65)
RP55
(110)
RP75
(187)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download   Download  
Gzipped Download   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.

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_1239 (release 3.0)
Previous IDs: none
Type: Family
Author: Bateman A
Number in seed: 25
Number in full: 416
Average length of the domain: 147.00 aa
Average identity of full alignment: 35 %
Average coverage of the sequence by the domain: 78.34 %

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 21.4 21.4
Trusted cut-off 21.5 21.5
Noise cut-off 21.2 21.3
Model length: 181
Family (HMM) version: 12
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 TIMP domain has been found. There are 18 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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