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.