| SMART accession number: | SM00217
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| Description: |
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| Interpro abstract (IPR008197): |
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. Whey acidic protein (WAP) is a major component of the whey fraction of milk, which contains a significant number of different proteins. WAP proteins share limited sequence identity, except for their conserved cysteine-rich regions, known as 4-disulphide core (4-DSC) domains, and the positional conservation of specific residues [(PUBMED:12751894)]. Several non-milk proteins also contain 4-DSC patterns, such as certain serine protease inhibitors. WAP itself appears to have a protease-inhibitor function, as seen with its inhibitory effect on the progression of cancer cells [(PUBMED:17215074)].
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| GO component: | extracellular region (GO:0005576) |
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| GO function: | peptidase inhibitor activity (GO:0030414) |
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| Family alignment: |
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Click on the following links for more information.
- Evolution (species in which this domain is found)
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- Literature (relevant references for this domain)
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Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.
- Kirchhoff C, Habben I, Ivell R, Krull N
- A major human epididymis-specific cDNA encodes a protein with sequence homology to extracellular proteinase inhibitors.
- Biol Reprod. 1991; 45: 350-7
- Display abstract
The amino acid sequence of a major human epididymis-specific protein was deduced from the nucleotide sequence of its cloned cDNA. The encoded product showed characteristics of a secretory protein, with a signal peptide followed by a small (approximately 10-kDa), acidic (pI 4.3), and cysteine-rich polypeptide. The positions of half-cysteines suggested that it was a two-domain member of the family of 'four-disulfide core' proteins to which a number of proteinase inhibitors belong. Southern blot analyses of human genomic DNA showed that the transcripts originated from a single copy gene. Northern blot and in situ transcript hybridization specifically localized the HE4 (human epididymis gene product) mRNA to the epithelial cells of the epididymal duct, predominantly within the distal sections. A possible function in sperm maturation as indicated by amino acid similarities to extracellular proteinase inhibitors of genital tract mucous secretions is discussed in the context of its tissue-specific transcription.
- Legouis R et al.
- The candidate gene for the X-linked Kallmann syndrome encodes a protein related to adhesion molecules.
- Cell. 1991; 67: 423-35
- Display abstract
Kallmann syndrome associates hypogonadotropic hypogonadism and anosmia and is probably due to a defect in the embryonic migration of olfactory and GnRH-synthesizing neurons. The Kallmann gene had been localized to Xp22.3. In this study 67 kb of genomic DNA, corresponding to a deletion interval containing at least part of the Kallmann gene, were sequenced. Two candidate exons, identified by multiparameter computer programs, were found in a cDNA encoding a protein of 679 amino acids. This candidate gene (ADMLX) is interrupted in its 3' coding region in the Kallmann patient, in which the proximal end of the KAL deletion interval was previously defined. A 5' end deletion was detected in another Kallmann patient. The predicted protein sequence shows homologies with the fibronectin type III repeat. ADMLX thus encodes a putative adhesion molecule, consistent with the defect of embryonic neuronal migration.
- Araki K, Kuwada M, Ito O, Kuroki J, Tachibana S
- Four disulfide bonds' allocation of Na+, K(+)-ATPase inhibitor (SPAI).
- Biochem Biophys Res Commun. 1990; 172: 42-6
- Display abstract
We have recently reported the primary structures of the three unique peptide inhibitors (SPAI-1, -2, and -3) against Na+, K(+)-ATPase which contained four disulfide bridges in common (Biochem. Biophys. Res. Commun. 164, 496 (1989)). The disulfide connectivities of SPAI were determined by the combination of amino acid analyses with the direct application to a gas-phase sequencer of its proteolytic fragments. The disulfide bond was identified by detection of phenylthiohydantoin derivatives of cystine and its decomposed product dehydroalanine. The four cysteine pairs were disclosed to be Cys20 to Cys49, Cys27 to Cys53, Cys36 to Cys48, and Cys42 to Cys57, all linked by disulfide bridge formation. The allocation pattern of these disulfide bonds was the same as that recently reported for human mucous proteinase inhibitor (EMBO J. 7, 345 (1988], though SPAI showed no proteinase inhibitory activity at all.
- Coronel CE, SanAgustin J, Lardy HA
- Purification and structure of caltrin-like proteins from seminal vesicle of the guinea pig.
- J Biol Chem. 1990; 265: 6854-9
- Display abstract
Two different small proteins that cross-react with the antiserum against bovine caltrin (calcium transport inhibitor) have been purified from the seminal vesicle contents of the guinea pig. The primary structure and some molecular characteristics of the pure proteins are reported. The two proteins interact with concanavalin A indicating the presence of carbohydrates in their molecules. Chemical deglycosylation with trifluoromethanesulfonic acid, after reduction and carboxymethylation, results in complete loss of affinity for the lectin. Removal of sugar components from the structure destroys the ability of caltrin-like proteins to react with antibodies to bovine caltrin. The protein moving faster on polyacrylamide gel electrophoresis is designated guinea pig caltrin I, the other is II. They contain 45 and 55 amino acids, and the molecular weights of the peptide portions are 5082 and 6255, respectively. Although they have entirely different amino acid sequences, they share some common features: recognition by rabbit antibodies to bovine caltrin, the predominance of basic residues and the presence of 3 cysteine residues in fraction I and 8 in fraction II. The proteins have pI values of 9.5 and 10.2, respectively, which are consistent with the amino acid composition. The two pure fractions are approximately equally effective, on a weight basis, as inhibitors of 45Ca2+ uptake by guinea pig spermatozoa. The data presented reinforce the hypothesis that caltrin-like proteins are responsible for the previously reported (Coronel, C.E., San Agustin, J., and Lardy, H.A. (1988) Biol. Reprod. 38, 713-722), calcium-transport inhibitor activity detected in reproductive tract fluid from adult male guinea pigs.
- Wiedow O, Schroder JM, Gregory H, Young JA, Christophers E
- Elafin: an elastase-specific inhibitor of human skin. Purification, characterization, and complete amino acid sequence.
- J Biol Chem. 1990; 265: 14791-5
- Display abstract
A potent inhibitor of human leukocyte elastase (EC 3.4.21.37) and porcine pancreatic elastase (EC 3.4.21.36) was purified to homogeneity from human horny layers. It inhibits human leukocyte elastase and porcine pancreatic elastase in a 1:1 molar ratio and shows equilibrium dissociation constants of 6 x 10(-10) M and 1 x 10(-9) M, respectively. Inhibition of plasmin, trypsin, alpha-chymotrypsin, and cathepsin G was not observed. This inhibitor proved to be an acid stable basic peptide with an isoelectric point of 9.7. The complete amino acid sequence appears to be unique with 38% homology to the C-terminal half of antileukoprotease. The sequence shows that the inhibitor is composed of 57 amino acids and predicts a Mr of 7017. The high affinity as well as the apparent specificity for elastases suggests a functional role in preventing elastase-mediated tissue proteolysis. It is suggested that the term "elafin" be used to designate this inhibitor.
- Dear TN, Ramshaw IA, Kefford RF
- Differential expression of a novel gene, WDNM1, in nonmetastatic rat mammary adenocarcinoma cells.
- Cancer Res. 1988; 48: 5203-9
- Display abstract
Subtractive hybridization was used to investigate differences in gene expression between a metastatic clone and nonmetastatic clone of the rat mammary adenocarcinoma line DMBA-8 which differ 100-fold in their metastatic behavior. Several differentially expressed highly homologous mRNAs (600 to 900 base pairs) were identified from the nonmetastatic line which are expressed at a level 20-fold higher than in the metastatic clone. Available sequence data show no homology to published gene sequences. There is no difference between the metastatic and nonmetastatic clones regarding DNA restriction fragment sizes or copy number of the gene. Expression of this newly described gene, named WDNM1, may be an important correlate of nonmetastasis in this tumor model.
- Hennighausen LG, Sippel AE
- Mouse whey acidic protein is a novel member of the family of 'four-disulfide core' proteins.
- Nucleic Acids Res. 1982; 10: 2677-84
- Display abstract
Unlike in other mammalian species, the major whey protein in mouse is not alpha-lactalbumin, but a cysteine rich, acidic protein with a molecular weight of 14.0 kDa. We have deduced the amino acid sequence of this mouse acidic of whey protein from the nucleotide sequence of cloned cDNA. The positions of the half cysteines suggest that mouse whey acidic protein (WAP) is a two domain protein, very similar in structure to the plant lectin wheat germ agglutinin and the hypothalamic carrier protein neurophysin.
- Structure (3D structures containing this domain)
3D Structures of WAP domains in PDB
| PDB code | Main view | Title | | 1fle |  | Crystal structure of elafin complexed with porcine pancreatic elastase |
| 1udk |  | Solution structure of nawaprin |
| 1zlg |  | Solution structure of the extracellular matrix protein anosmin-1 |
| 2rel |  | Solution structure of r-elafin, a specific inhibitor of elastase, nmr, 11 structures |
| 2z7f |  | Crystal structure of the complex of human neutrophil elastase with 1/2slpi |
- Links (links to other resources describing this domain)
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