Summary: Kunitz/Bovine pancreatic trypsin inhibitor domain
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Kunitz domain Edit Wikipedia article
|Kunitz/Bovine pancreatic trypsin inhibitor domain|
Kunitz domains are the active domains of proteins that inhibit the function of protein degrading enzymes or, more specifically, domains of Kunitz-type are protease inhibitors. They are relatively small with a length of about 50 to 60 amino acids and a molecular weight of 6 kDa. Examples of Kunitz-type protease inhibitors are aprotinin (bovine pancreatic trypsin inhibitor, BPTI), Alzheimer's amyloid precursor protein (APP), and tissue factor pathway inhibitor (TFPI).
The structure is a disulfide rich alpha+beta fold. Bovine pancreatic trypsin inhibitor is an extensively studied model structure. Certain family members are similar to the tick anticoagulant peptide (TAP, ). This is a highly selective inhibitor of factor Xa in the blood coagulation pathways. TAP molecules are highly dipolar, and are arranged to form a twisted two-stranded antiparallel beta sheet followed by an alpha helix.
The majority of the sequences having this domain belong to the MEROPS inhibitor family I2, clan IB; the Kunitz/bovine pancreatic trypsin inhibitor family, they inhibit proteases of the S1 family and are restricted to the metazoa with a single exception: Amsacta moorei entomopoxvirus, a species of poxvirus. They are short (about 50 to 60 amino acid residues) alpha/beta proteins with few secondary structures. The fold is constrained by three disulfide bonds. The type example for this family is BPTI (or basic protease inhibitor), but the family includes numerous other members, such as snake venom basic protease; mammalian inter-alpha-trypsin inhibitors; trypstatin, a rat mast cell inhibitor of trypsin; a domain found in an alternatively spliced form of Alzheimer's amyloid beta-protein; domains at the C-termini of the alpha-1 and alpha-3 chains of type VI and type VII collagens; tissue factor pathway inhibitor precursor; and Kunitz STI protease inhibitor contained in legume seeds.
Kunitz domains are stable as standalone peptides, able to recognise specific protein structures, and also work as competitive protease inhibitors in their free form. These properties have led to attempts at developing biopharmaceutical drugs from Kunitz domains. Candidate domains are selected from molecular libraries containing over 10 million variants with the aid of display techniques like phage display, and can be produced in large scale by genetically engineered organisms.
The first of these drugs to be marketed was the kallikrein inhibitor ecallantide, used for the treatment of hereditary angioedema. It was approved in the United States in 2009. Another example is depelestat, an inhibitor of neutrophil elastase that has undergone Phase II clinical trials for the treatment of acute respiratory distress syndrome in 2006/2007 and has also been described as a potential inhalable cystic fibrosis treatment.
Human proteins containing this domain include:
- AMBP, APLP2, APP
- COL6A3, COL7A1, COL28A1
- SPINLW1, SPINT1, SPINT2, SPINT3, SPINT4
- TFPI, TFPI2
- WFDC6, WFDC8, WFIKKN1, WFIKKN2
- doi:10.1107/S0907444902007333. PMID 12077460.; Arnoux B, Ducruix A, Prangé T (July 2002). "Anisotropic behaviour of the C-terminal Kunitz-type domain of the alpha3 chain of human type VI collagen at atomic resolution (0.9 Å)". Acta Crystallogr. D Biol. Crystallogr. 58 (Pt 7): 1252–4.
- Nixon, AE; Wood, CR (2006). "Engineered protein inhibitors of proteases". Current opinion in drug discovery & development 9 (2): 261–8. PMID 16566296.
- Antuch W, Güntert P, Billeter M, Hawthorne T, Grossenbacher H, Wüthrich K (September 1994). "NMR solution structure of the recombinant tick anticoagulant protein (rTAP), a factor Xa inhibitor from the tick Ornithodoros moubata". FEBS Lett. 352 (2): 251–7. doi:10.1016/0014-5793(94)00941-4. PMID 7925983.
- St Charles R, Padmanabhan K, Arni RV, Padmanabhan KP, Tulinsky A (February 2000). "Structure of tick anticoagulant peptide at 1.6 A resolution complexed with bovine pancreatic trypsin inhibitor". Protein Sci. 9 (2): 265–72. doi:10.1110/ps.9.2.265. PMC 2144540. PMID 10716178.
- Rawlings ND, Barrett AJ, Tolle DP (2004). "Evolutionary families of peptidase inhibitors". Biochem. J. 378 (Pt 3): 705–16. doi:10.1042/BJ20031825. PMC 1224039. PMID 14705960.
- Wlodawer A, Housset D, Kim KS, Fuchs J, Woodward C (1991). "Crystal structure of a Y35G mutant of bovine pancreatic trypsin inhibitor". J. Mol. Biol. 220 (3): 757–770. doi:10.1016/0022-2836(91)90115-M. PMID 1714504.
- Salier JP (1990). "Inter-alpha-trypsin inhibitor: emergence of a family within the Kunitz-type protease inhibitor superfamily". Trends Biochem. Sci. 15 (11): 435–439. doi:10.1016/0968-0004(90)90282-G. PMID 1703675.
- Takahashi K, Ikeo K, Gojobori T (1992). "Evolutionary origin of a Kunitz-type trypsin inhibitor domain inserted in the amyloid beta precursor protein of Alzheimer's disease". J. Mol. Evol. 34 (6): 536–543. doi:10.1007/BF00160466. PMID 1593645.
- Sprecher CA, Foster DC, Kisiel W, Mathewes S (1994). "Molecular cloning, expression, and partial characterization of a second human tissue-factor-pathway inhibitor". Proc. Natl. Acad. Sci. U.S.A. 91 (8): 3353–3357. doi:10.1073/pnas.91.8.3353. PMC 43575. PMID 8159751.
- Biemann K, Papayannopoulos IA (1992). "Amino acid sequence of a protease inhibitor isolated from Sarcophaga bullata determined by mass spectrometry". Protein Sci. 1 (2): 278–288. doi:10.1002/pro.5560010210. PMC 2142190. PMID 1304909.
- Lehmann, A (2008). "Ecallantide (DX-88), a plasma kallikrein inhibitor for the treatment of hereditary angioedema and the prevention of blood loss in on-pump cardiothoracic surgery". Expert opinion on biological therapy 8 (8): 1187–99. doi:10.1517/14712522.214.171.1247. PMID 18613770.
- Dyax Corp. (2009). "Full prescibing information Kalbitor" (PDF). Retrieved 2010-05-02.
- Clinical trial number NCT00455767 for "Safety and Efficacy Study of Depelestat in Acute Respiratory Distress Syndrome (ARDS) Patients" at ClinicalTrials.gov
- Attucci, S; Gauthier, A; Korkmaz, B; Delépine, P; Martino, MF; Saudubray, F; Diot, P; Gauthier, F (2006). "EPI-hNE4, a proteolysis-resistant inhibitor of human neutrophil elastase and potential anti-inflammatory drug for treating cystic fibrosis". The Journal of Pharmacology and Experimental Therapeutics 318 (2): 803–9. doi:10.1124/jpet.106.103440. PMID 16627747.
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Kunitz/Bovine pancreatic trypsin inhibitor domain Provide feedback
Indicative of a protease inhibitor, usually a serine protease inhibitor. Structure is a disulfide rich alpha+beta fold. BPTI (bovine pancreatic trypsin inhibitor) is an extensively studied model structure. Certain family members are similar to the tick anticoagulant peptide (TAP, P17726). This is a highly selective inhibitor of factor Xa in the blood coagulation pathways . TAP molecules are highly dipolar  and are arranged to form a twisted two- stranded antiparallel beta-sheet followed by an alpha helix .
Antuch W, Guntert P, Billeter M, Hawthorne T, Grossenbacher H, Wuthrich K; , FEBS Lett 1994;352:251-257.: NMR solution structure of the recombinant tick anticoagulant protein (rTAP), a factor Xa inhibitor from the tick Ornithodoros moubata. PUBMED:7925983 EPMC:7925983
St Charles R, Padmanabhan K, Arni RV, Padmanabhan KP, Tulinsky A; , Protein Sci 2000;9:265-272.: Structure of tick anticoagulant peptide at 1.6 A resolution complexed with bovine pancreatic trypsin inhibitor. PUBMED:10716178 EPMC:10716178
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR002223
The majority of the sequences having this domain belong to the MEROPS inhibitor family I2, clan IB; the Kunitz/bovine pancreatic trypsin inhibitor family, they inhibit proteases of the S1 family [PUBMED:14705960] and are restricted to the metazoa with a single exception: Amsacta moorei entomopoxvirus. They are short (~50 residue) alpha/beta proteins with few secondary structures. The fold is constrained by 3 disulphide bonds. The type example for this family is aprotinin (bovine pancreatic trypsin inhibitor) [PUBMED:1714504] (or basic protease inhibitor), but the family includes numerous other members [PUBMED:1703675, PUBMED:1593645, PUBMED:8159751, PUBMED:1304909], such as snake venom basic protease; mammalian inter-alpha-trypsin inhibitors; trypstatin, a rodent mast cell inhibitor of trypsin; a domain found in an alternatively-spliced form of Alzheimer's amyloid beta-protein; domains at the C-termini of the alpha(1) and alpha(3) chains of type VII and type VI collagens; and tissue factor pathway inhibitor precursor.
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function||serine-type endopeptidase inhibitor activity (GO:0004867)|
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
- the number of sequences which exhibit this architecture
a textual description of the architecture, e.g. Gla, EGF x 2, Trypsin.
This example describes an architecture with one
Gladomain, followed by two consecutive
EGFdomains, and finally a single
- a link to the page in the Pfam site showing information about the sequence that the graphic describes
- the UniProt description of the protein sequence
- the number of residues in the sequence
- the Pfam graphic itself.
Note that you can see the family page for a particular domain by clicking on the graphic. You can also choose to see all sequences which have a given architecture by clicking on the Show link in each row.
Finally, because some families can be found in a very large number of architectures, we load only the first fifty architectures by default. If you want to see more architectures, click the button at the bottom of the page to load the next set.
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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...
There are various ways to view or download the sequence alignments that we store. We provide several sequence viewers and a plain-text Stockholm-format file for download.
We make a range of alignments for each Pfam-A family:
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- the alignment generated by searching the sequence database using the HMM
- Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
- alignment generated by searching the NCBI sequence database using the family HMM
- alignment generated by searching the metagenomics sequence database using the family HMM
You can see the alignments as HTML or in three different sequence viewers:
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You can download (or view in your browser) a text representation of a Pfam alignment in various formats:
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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.
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
Format an alignment
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.
You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
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 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...
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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.
|Number in seed:||100|
|Number in full:||8677|
|Average length of the domain:||53.30 aa|
|Average identity of full alignment:||34 %|
|Average coverage of the sequence by the domain:||20.51 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 80369284 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||19|
|Download:||download the raw HMM for this family|
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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the 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, its 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:
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".
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.
The tree shows the occurrence of this domain across different species. More...
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.
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:
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There are 7 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
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 Kunitz_BPTI domain has been found. There are 245 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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