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27  structures 332  species 3  interactions 5759  sequences 370  architectures

Family: WAP (PF00095)

Summary: WAP-type (Whey Acidic Protein) 'four-disulfide core'

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This is the Wikipedia entry entitled "Whey Acidic Protein". More...

Whey Acidic Protein Edit Wikipedia article

PDB 2rel EBI.jpg
R-elafin, a specific inhibitor of elastase
(11 NMR structures, PDB: 2REL​)
Symbol WAP
Pfam PF00095
Pfam clan CL0454
InterPro IPR008197
SCOP 1fle
TCDB 1.C.15

In molecular biology, the protein domain Whey acidic protein (WAP) has been identified as a major whey protein in milk and is important in regulating the proliferation of mammary epithelial cells. Additionally, its physiological function is thought to be similar to a protease inhibitor. It has been concluded, therefore, that WAP regulates the proliferation of mammary epithelial cells by preventing elastase-type serine proteases from carrying out laminin degradation and by suppressing the MAP kinase signal pathway in the cell cycle.[1]

Production in mammals

Whey Acidic Protein(WAP) is the major milk protein in certain mammals. There are exceptions in some mammalian species, whereby WAP has not been found to be synthesized in the mammary gland.[1]

WAP motif and cancer

There have been several candidate markers for cancer; most notably genes coding for elafin, antileukoproteinase 1 (previously called secretory leucocyte proteinase inhibitor, SLPI), WAP four disulphide core domain protein 1 (previously called prostate stromal protein 20 kDa, PS20), and WAP four disulphide core domain protein 2 (previously called major human epididymis-specific protein E4, HE4). These genes can be useful biomarkers for detecting tumours.[2]

Biochemistry of WAP motifs

Whey Acidic Protein contains two to three four-disulfide core domain, also termed WAP domain or WAP motif. Each disulfide bond of the WAP motif is made up of two cysteine molecule. This motif is also found in other proteins of different functions, which led to the suggestion that WAP is associated with antiprotease or antibacterial properties. The following schematic representation shows the position of the conserved cysteines that form the 'four-disulfide core' WAP domain

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

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

  • WAP-type [1] 'four-disulfide core' domain in PROSITE

It has been found that humans and ruminants have the WAP gene in their genome as pseudogene. Although humans and ruminants do not seem to encode the gene, there is no detrimental effect. However, mouse pups feeding on maternal milk lacking Whey Acidic Protein has been associated with poor growth rate and lethality.


  1. ^ a b Seki M, Matsura R, Iwamori T, Nukumi N, Yamanouchi K, Kano K, et al. (2012). "Identification of whey acidic protein (WAP) in dog milk". Exp Anim. 61 (1): 67–70. PMID 22293674. 
  2. ^ Bouchard D, Morisset D, Bourbonnais Y, Tremblay GM (2006). "Proteins with whey-acidic-protein motifs and cancer". Lancet Oncol. 7 (2): 167–74. doi:10.1016/S1470-2045(06)70579-4. PMID 16455481. 

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WAP-type (Whey Acidic Protein) 'four-disulfide core' Provide feedback

WAP belongs to the group of Elafin or elastase-specific inhibitors.

Literature references

  1. Tsunemi M, Matsuura Y, Sakakibara S, Katsube Y;, Biochemistry. 1996;35:11570-11576.: Crystal structure of an elastase-specific inhibitor elafin complexed with porcine pancreatic elastase determined at 1.9 A resolution. PUBMED:8794736 EPMC:8794736

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR008197

The four-disulfide core (4-DSC) or WAP domain comprises eight cysteine residues involved in disulfide bonds in a conserved arrangement [PUBMED:6896234]. The four disulphide core containing Whey Acidic Proteins (WAP) are the major whey proteins in the milk of many mammals and are considered to be the prototypic members of the family. However the WAP domain is not exclusive to WAP proteins, but it is found in many other proteins, a number of which have been shown to exhibit antiproteinase function [PUBMED:11965550].

One or more of the WAP domains occur in the WDNM1 protein, which is involved in the metastatic potential of adenocarcinomas in rats [PUBMED:3136918]; Kallmann syndrome protein [PUBMED:1913827]; caltrin-like protein II from guinea pig [PUBMED:2324101], which inhibits calcium transport into spermatozoa; elafin, a serine elastase inhibitor which belongs to MEROPS inhibitor family I17 [PUBMED:2394696]; and papilin, a metalloendopeptidase inhibitor which belongs to MEROPS inhibitor family I2 and is effective against procollagen N-proteinase [PUBMED:11076767].

Gene Ontology

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Domain organisation

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Seed source: Swissprot_feature_table
Previous IDs: wap;
Type: Domain
Sequence Ontology: SO:0000417
Author: Sonnhammer ELL
Number in seed: 483
Number in full: 5759
Average length of the domain: 44.60 aa
Average identity of full alignment: 34 %
Average coverage of the sequence by the domain: 14.36 %

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HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 47079205 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 20.8 20.8
Trusted cut-off 20.8 20.8
Noise cut-off 20.7 20.7
Model length: 41
Family (HMM) version: 22
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There are 3 interactions for this family. More...

Trypsin Cementoin WAP


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 WAP domain has been found. There are 27 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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