PROSITE documentation PDOC00026
WAP-type 'four-disulfide core' domain profile


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>).

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

'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.

Expert(s) to contact by email:

Claverie J.-M.

Last update:

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


Technical section

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

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


1AuthorsHennighausen L.G. Sippel A.E.
TitleMouse whey acidic protein is a novel member of the family of 'four-disulfide core' proteins.
SourceNucleic Acids Res. 10:2677-2684(1982).
PubMed ID6896234

2AuthorsWiedow O. Schroeder J.-M. Gregory H. Young J.A. Christophers E.
TitleElafin: an elastase-specific inhibitor of human skin. Purification, characterization, and complete amino acid sequence.
SourceJ. Biol. Chem. 265:14791-14795(1990).
PubMed ID2394696

3AuthorsFrancart C. Dauchez M. Alix A.J. Lippens G.
TitleSolution structure of R-elafin, a specific inhibitor of elastase.
SourceJ. Mol. Biol. 268:666-677(1997).
PubMed ID9171290

4AuthorsAraki K. Kuwada M. Ito O. Kuroki J. Tachibana S.
TitleFour disulfide bonds' allocation of Na+, K(+)-ATPase inhibitor (SPAI).
SourceBiochem. Biophys. Res. Commun. 172:42-46(1990).
PubMed ID2171523

5AuthorsLegouis 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.
TitleThe candidate gene for the X-linked Kallmann syndrome encodes a protein related to adhesion molecules.
SourceCell 67:423-435(1991).
PubMed ID1913827

6AuthorsHu Y. Sun Z. Eaton J.T. Bouloux P.M. Perkins S.J.
TitleExtended and flexible domain solution structure of the extracellular matrix protein anosmin-1 by X-ray scattering, analytical ultracentrifugation and constrained modelling.
SourceJ. Mol. Biol. 350:553-570(2005).
PubMed ID15949815

7AuthorsSimpson K.J. Ranganathan S. Fisher J.A. Janssens P.A. Shaw D.C. Nicholas K.R.
TitleThe gene for a novel member of the whey acidic protein family encodes three four-disulfide core domains and is asynchronously expressed during lactation.
SourceJ. Biol. Chem. 275:23074-23081(2000).
PubMed ID10801834

8AuthorsNair D.G. Fry B.G. Alewood P. Kumar P.P. Kini R.M.
TitleAntimicrobial activity of omwaprin, a new member of the waprin family of snake venom proteins.
SourceBiochem. J. 402:93-104(2007).
PubMed ID17044815

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