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The 'four-disulfide core' or WAP domain comprises 8 cysteine residues involved in disulfide bonds in a conserved arrangement [1]. One or more of these domains occur in whey acidic protein (WAP), antileukoproteinase, elastase-inhibitor proteins and other structurally related proteins which are listed below.

• Whey acidic protein (WAP). WAP is a major component of milk whey whose function might be that of a protease inhibitor. WAP consists of two 'four-disulfide core' domains in most mammals.
• Antileukoproteinase 1 (HUSI), a mucous fluid serine proteinase inhibitor. HUSI consists of two 'four-disulfide core' domains.
• Elafin, an elastase-specific inhibitor from human skin [2,3].
• Sodium/potassium ATPase inhibitors SPAI-1, -2, and -3 from pig [4].
• Chelonianin, a protease inhibitor from the eggs of red sea turtle. This inhibitor consists of two domains: an N-terminal domain which inhibits trypsin and belongs to the BPTI/Kunitz family of inhibitors, and a C-terminal domain which inhibits subtilisin and is a 'four-disulfide core domain'.
• Extracellular peptidase inhibitor (WDNM1 protein), involved in the metastatic potential of adenocarcinomas in rats.
• Caltrin-like protein 2 from guinea pig, which inhibits calcium transport into spermatozoa.
• Kallmann syndrome protein (Anosmin-1 or KALIG-1) [5,6]. This secreted protein may be a adhesion-like molecule with anti-protease activity. It contains a 'four-disulfide core domain' in its N-terminal part.
• Whey acidic protein (WAP) from the tammar wallaby, which consists of three 'four-disulfide core' domains [7].
• Waprins from snake venom, such as omwaprin from Oxyuranus microlepidotus [8] which has antibacterial activity against Gram-positive bacteria.

The following schematic representation shows the position of the conserved cysteines that form the 'four-disulfide core' WAP domain (see <PDB:2REL>).

                           +---------------------+
                           |    +-----------+    |
                           |    |           |    |
         xxxxxxxCPxxxxxxxxxCxxxxCxxxxxCxxxxxCCxxxCxxxCxxxx
                |                     |      |       |
                |                     +--------------+
                |                            |
                +----------------------------+

         <------------------50-residues------------------>

'C': conserved cysteine involved in a disulfide bond.

We developed a profile that covers the whole structure of the WAP-type 'four-disulfide core' domain.

Claverie J.-M.

July 2008 / Pattern removed, profile added and text revised.

PROSITE method (with tools and information) covered by this documentation:

WAP, PS51390; WAP-type 'four-disulfide core' domain profile  (MATRIX)

Sequences known to belong to this class detected by the profile: ALL Other sequence(s) detected in Swiss-Prot: NONE.

• Domain architecture view of Swiss-Prot proteins matching PS51390 • Retrieve an alignment of Swiss-Prot true positive hits:   Clustal format, color, condensed view  / Clustal format, color  / Clustal format, plain text  / Fasta format • Retrieve the sequence logo from the alignment • Taxonomic tree view of all Swiss-Prot/TrEMBL entries matching PS51390 • Retrieve a list of all Swiss-Prot/TrEMBL entries matching PS51390 • Scan Swiss-Prot/TrEMBL entries against PS51390 • view ligand binding statistics

Matching PDB structures: 1CJH 1FLE 1TWP 1UDK ... [ALL]

1	Authors	Hennighausen L.G., Sippel A.E.
	Title	Mouse whey acidic protein is a novel member of the family of 'four-disulfide core' proteins.
	Source	Nucleic Acids Res. 10:2677-2684(1982).
	PubMed ID	6896234

2	Authors	Wiedow O., Schroeder J.-M., Gregory H., Young J.A., Christophers E.
	Title	Elafin: an elastase-specific inhibitor of human skin. Purification, characterization, and complete amino acid sequence.
	Source	J. Biol. Chem. 265:14791-14795(1990).
	PubMed ID	2394696

3	Authors	Francart C., Dauchez M., Alix A.J., Lippens G.
	Title	Solution structure of R-elafin, a specific inhibitor of elastase.
	Source	J. Mol. Biol. 268:666-677(1997).
	PubMed ID	9171290
	DOI	10.1006/jmbi.1997.0983

4	Authors	Araki K., Kuwada M., Ito O., Kuroki J., Tachibana S.
	Title	Four disulfide bonds' allocation of Na+, K(+)-ATPase inhibitor (SPAI).
	Source	Biochem. Biophys. Res. Commun. 172:42-46(1990).
	PubMed ID	2171523

5	Authors	Legouis R., Hardelin J.-P., Levilliers J., Claverie J.-M., Compain S., Wunderle V., Millasseau P., Le Paslier D., Cohen D., Caterina D. Bougueleret L., Delemarre-Van de Waal H., Lutfalla G., Weissenbach J., Petit C.
	Title	The candidate gene for the X-linked Kallmann syndrome encodes a protein related to adhesion molecules.
	Source	Cell 67:423-435(1991).
	PubMed ID	1913827

6	Authors	Hu Y., Sun Z., Eaton J.T., Bouloux P.M., Perkins S.J.
	Title	Extended and flexible domain solution structure of the extracellular matrix protein anosmin-1 by X-ray scattering, analytical ultracentrifugation and constrained modelling.
	Source	J. Mol. Biol. 350:553-570(2005).
	PubMed ID	15949815
	DOI	10.1016/j.jmb.2005.04.031

7	Authors	Simpson K.J., Ranganathan S., Fisher J.A., Janssens P.A., Shaw D.C., Nicholas K.R.
	Title	The gene for a novel member of the whey acidic protein family encodes three four-disulfide core domains and is asynchronously expressed during lactation.
	Source	J. Biol. Chem. 275:23074-23081(2000).
	PubMed ID	10801834
	DOI	10.1074/jbc.M002161200

8	Authors	Nair D.G., Fry B.G., Alewood P., Kumar P.P., Kini R.M.
	Title	Antimicrobial activity of omwaprin, a new member of the waprin family of snake venom proteins.
	Source	Biochem. J. 402:93-104(2007).
	PubMed ID	17044815
	DOI	10.1042/BJ20060318

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