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49  structures 567  species 0  interactions 20608  sequences 722  architectures

Family: Kazal_2 (PF07648)

Summary: Kazal-type serine protease inhibitor domain

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This is the Wikipedia entry entitled "Kazal domain". More...

Kazal domain Edit Wikipedia article

Kazal-type serine protease inhibitor domain
PDB 2b0u EBI.jpg
the structure of the follistatin:activin complex
Kazal-type serine protease inhibitor domain
PDB 1lr9 EBI.jpg
structure of fs1, the heparin-binding domain of follistatin

The Kazal 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.

In animals, serine protease inhibitors that act via their Kazal domain are grouped under the MEROPS inhibitor family I1, clan IA.[1][2]

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).[3] 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.[4][5]

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.[4] The inhibitor makes 11 contacts with its enzyme substrate: unusually, 8 of these important residues are hypervariable.[5] 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.[5][6] 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.

Human proteins with Kazal 1 domains:

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.[7][8][9] The amino terminal segment of this domain binds to the active site of its target proteases, thus inhibiting their function.

Human proteins with Kazal 2 domains:


  1. ^ MEROPS family I1
  2. ^ InterProIPR001239
  3. ^ 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.
  4. ^ 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.
  5. ^ 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.
  6. ^ 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.
  7. ^ 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.
  8. ^ 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.
  9. ^ 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

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.

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.

Internal database links

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR002350

Canonical serine proteinase inhibitors are distributed in a wide range of organisms from all kingdoms of life and play crucial role in various physiological mechanisms [ PUBMED:6996568 ]. They interact from the canonical proteinase-inhibitor binding loop, where P1 residue has a predominant role (the residue at the P1 position contributing the carbonyl portion to the reactive-site peptide bond). These so-called canonical inhibitors bind to their cognate enzymes in the same manner as a good substrate, but are cleaved extremely slowly. Kazal-type inhibitors represent the most studied canonical proteinase inhibitors. Kazal inhibitors are extremely variable at their reactive sites. However, some regularity prevails such as the presence of lysine at position P1 indicating strong inhibition of trypsin [ PUBMED:10708867 ].

The Kazal inhibitor has six cysteine residues engaged in disulfide bonds arranged as shown in the following schematic representation:

                       |                  |
                |              |             |                 |
                |              +-------------|-----------------+

'C': conserved cysteine involved in a disulfide bond.
'#': active site residue.
'*': position of the pattern.

The structure of classical Kazal domains consists of a central alpha helix, which is inserted between two beta-strands and a third that is toward the C terminus [ PUBMED:6752426 ]. The reactive site P1 and the conformation of the reactive site loop is structurally highly conserved, similar to the canonical conformation of small serine proteinase inhibitors.

This entry represents the Kazal domain.

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 3 members:

Kazal_1 Kazal_2 Kazal_3


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Curation and family details

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Seed source: Manual
Previous IDs: none
Type: Domain
Sequence Ontology: SO:0000417
Author: Finn RD
Number in seed: 40
Number in full: 20608
Average length of the domain: 47.20 aa
Average identity of full alignment: 30 %
Average coverage of the sequence by the domain: 13.52 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 57096847 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 22.8 11.0
Trusted cut-off 22.8 11.0
Noise cut-off 22.7 10.9
Model length: 49
Family (HMM) version: 17
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Species distribution

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Archea Archea Eukaryota Eukaryota
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Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence


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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_2 domain has been found. There are 49 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 sequence.

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