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88  structures 356  species 6  interactions 1792  sequences 207  architectures

Family: Kazal_1 (PF00050)

Summary: Kazal-type serine protease inhibitor domain

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This is the Wikipedia entry entitled "Kazal-type serine protease inhibitor domain". More...

Kazal-type serine protease inhibitor domain Edit Wikipedia article

Kazal-type serine protease inhibitor domain
PDB 2b0u EBI.jpg
the structure of the follistatin:activin complex
Identifiers
Symbol Kazal_1
Pfam PF00050
InterPro IPR002350
PROSITE PDOC00254
SCOP 3sgb
SUPERFAMILY 3sgb
Kazal-type serine protease inhibitor domain
PDB 1lr9 EBI.jpg
structure of fs1, the heparin-binding domain of follistatin
Identifiers
Symbol Kazal_2
Pfam PF07648
InterPro IPR011497
PROSITE PDOC00254
SCOP 3sgb
SUPERFAMILY 3sgb

Kazal-type serine protease inhibitor domain is an evolutionary conserved protein domain.

Usually indicative of serine protease inhibitors. However, kazal-like domains are also seen in the extracellular part of agrins, which are not known to be protease inhibitors.

Kazal_1

Kazal domains often occur in tandem arrays. Small alpha+beta fold containing three disulfide bonds. Alignment also includes a single domain from transporters in the OATP/PGT family P46721.

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.

This family of Kazal inhibitors, belongs to MEROPS inhibitor family I1, clan IA. They inhibit serine peptidases of the S1 family (INTERPRO).[1] The members are primarily metazoan, but includes exceptions in the alveolata (apicomplexa), stramenopiles, higher plants and bacteria.

Kazal inhibitors, which inhibit a number of serine proteases (such as trypsin and elastase), belong to family of proteins that includes pancreatic secretory trypsin inhibitor; avian ovomucoid; acrosin inhibitor; and elastase inhibitor. These proteins contain between 1 and 7 Kazal-type inhibitor repeats.[2][3]

The structure of the Kazal repeat includes a large quantity of extended chain, 2 short alpha-helices and a 3-stranded anti-parallel beta sheet.[2] The inhibitor makes 11 contacts with its enzyme substrate: unusually, 8 of these important residues are hypervariable.[3] Altering the enzyme-contact residues, and especially that of the active site bond, affects the strength of inhibition and specificity of the inhibitor for particular serine proteases.[3][4] The presence of this Pfam domain is usually indicative of serine protease inhibitors, however, Kazal-like domains are also seen in the extracellular part of agrins which are not known to be proteinase inhibitors.

Kazal_2

This domain is usually indicative of serine protease inhibitors that belong to Merops inhibitor families: I1, I2, I17 and I31. However, kazal-like domains are also seen in the extracellular part of agrins, which are not known to be protease inhibitors. Kazal domains often occur in tandem arrays and have a central alpha-helix, a short two-stranded antiparallel beta-sheet and several disulphide bonds.[5][6][7] The amino terminal segment of this domain binds to the active site of its target proteases, thus inhibiting their function.

Subfamilies

  • Proteinase inhibitor I1, Kazal metazoa IPR001239

Examples

Human genes encoding proteins containing Kazal-type domains include:

Kazal_1

Kazal_2

References

  1. ^ Rawlings ND, Tolle DP, Barrett AJ (March 2004). "Evolutionary families of peptidase inhibitors". Biochem. J. 378 (Pt 3): 705–16. doi:10.1042/BJ20031825. PMC 1224039. PMID 14705960. 
  2. ^ a b Williamson MP, Marion D, Wüthrich K (March 1984). "Secondary structure in the solution conformation of the proteinase inhibitor IIA from bull seminal plasma by nuclear magnetic resonance". J. Mol. Biol. 173 (3): 341–59. doi:10.1016/0022-2836(84)90125-6. PMID 6699915. 
  3. ^ a b c Laskowski M, Kato I, Ardelt W, Cook J, Denton A, Empie MW, Kohr WJ, Park SJ, Parks K, Schatzley BL (January 1987). "Ovomucoid third domains from 100 avian species: isolation, sequences, and hypervariability of enzyme-inhibitor contact residues". Biochemistry 26 (1): 202–21. doi:10.1021/bi00375a028. PMID 3828298. 
  4. ^ Empie MW, Laskowski M (May 1982). "Thermodynamics and kinetics of single residue replacements in avian ovomucoid third domains: effect on inhibitor interactions with serine proteinases". Biochemistry 21 (10): 2274–84. doi:10.1021/bi00539a002. PMID 7046785. 
  5. ^ Schlott B, Wöhnert J, Icke C, Hartmann M, Ramachandran R, Gührs KH, Glusa E, Flemming J, Görlach M, Grosse F, Ohlenschläger O (April 2002). "Interaction of Kazal-type inhibitor domains with serine proteinases: biochemical and structural studies". J. Mol. Biol. 318 (2): 533–46. doi:10.1016/S0022-2836(02)00014-1. PMID 12051857. 
  6. ^ Stubbs MT, Morenweiser R, Stürzebecher J, Bauer M, Bode W, Huber R, Piechottka GP, Matschiner G, Sommerhoff CP, Fritz H, Auerswald EA (August 1997). "The three-dimensional structure of recombinant leech-derived tryptase inhibitor in complex with trypsin. Implications for the structure of human mast cell tryptase and its inhibition". J. Biol. Chem. 272 (32): 19931–7. doi:10.1074/jbc.272.32.19931. PMID 9242660. 
  7. ^ van de Locht A, Lamba D, Bauer M, Huber R, Friedrich T, Kröger B, Höffken W, Bode W (November 1995). "Two heads are better than one: crystal structure of the insect derived double domain Kazal inhibitor rhodniin in complex with thrombin". EMBO J. 14 (21): 5149–57. PMC 394622. PMID 7489704. 

This article incorporates text from the public domain Pfam and InterPro IPR002350 This article incorporates text from the public domain Pfam and InterPro IPR011497

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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.

Kazal-type serine protease inhibitor domain Provide feedback

Usually indicative of serine protease inhibitors. However, kazal-like domains are also seen in the extracellular part of agrins, which are not known to be protease inhibitors. Kazal domains often occur in tandem arrays. Small alpha+beta fold containing three disulphides. Alignment also includes a single domain from transporters in the OATP/PGT family P46721.

Internal database links

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR002350

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.

This family of Kazal inhibitors, belongs to MEROPS inhibitor family I1, clan IA. They inhibit serine peptidases of the S1 family (INTERPRO) [PUBMED:14705960]. The members are primarily metazoan, but includes exceptions in the alveolata (apicomplexa), stramenopiles, higher plants and bacteria.

Kazal inhibitors, which inhibit a number of serine proteases (such as trypsin and elastase), belong to family of proteins that includes pancreatic secretory trypsin inhibitor; avian ovomucoid; acrosin inhibitor; and elastase inhibitor. These proteins contain between 1 and 7 Kazal-type inhibitor repeats [PUBMED:6699915, PUBMED:3828298].

The structure of the Kazal repeat includes a large quantity of extended chain, 2 short alpha-helices and a 3-stranded anti-parallel beta sheet [PUBMED:6699915].The inhibitor makes 11 contacts with its enzyme substrate: unusually, 8 of these important residues are hypervariable [PUBMED:3828298]. Altering the enzyme-contact residues, and especially that of the active site bond, affects the the strength of inhibition and specificity of the inhibitor for particular serine proteases [PUBMED:3828298, PUBMED:7046785]. The presence of this Pfam domain is usually indicative of serine protease inhibitors, however, Kazal-like domains are also seen in the extracellular part of agrins which are not known to be proteinase inhibitors.

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 Kazal (CL0005), which has the following description:

Kazal domains are found in both serine protease inhibitors and extracellular regions of agrins. The structure of the Kazal domain is a small alpha/beta fold. Typically the Kazal domain consists of 2 short-helices and a 3-stranded anti-parallel sheet. The fold is contains several disulphide bonds.

The clan contains the following 2 members:

Kazal_1 Kazal_2

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
(51)
Full
(1792)
Representative proteomes NCBI
(4387)
Meta
(283)
RP15
(276)
RP35
(378)
RP55
(621)
RP75
(938)
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Format an alignment

  Seed
(51)
Full
(1792)
Representative proteomes NCBI
(4387)
Meta
(283)
RP15
(276)
RP35
(378)
RP55
(621)
RP75
(938)
Alignment:
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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
(51)
Full
(1792)
Representative proteomes NCBI
(4387)
Meta
(283)
RP15
(276)
RP35
(378)
RP55
(621)
RP75
(938)
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.

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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: Prosite
Previous IDs: kazal;
Type: Domain
Author: Eddy SR
Number in seed: 51
Number in full: 1792
Average length of the domain: 52.00 aa
Average identity of full alignment: 31 %
Average coverage of the sequence by the domain: 19.67 %

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 20.7 20.7
Trusted cut-off 20.7 20.7
Noise cut-off 20.6 20.6
Model length: 48
Family (HMM) version: 16
Download: download the raw HMM for this family

Species distribution

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Interactions

There are 6 interactions for this family. More...

PRKCSH Trypsin TGF_beta Kazal_1 FOLN Peptidase_S8

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 Kazal_1 domain has been found. There are 88 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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