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5  structures 164  species 1  interaction 1589  sequences 122  architectures

Family: WAP (PF00095)

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

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Whey Acidic Protein Edit Wikipedia article

WAP
PDB 2rel EBI.jpg
solution structure of r-elafin, a specific inhibitor of elastase, nmr, 11 structures
Identifiers
Symbol WAP
Pfam PF00095
Pfam clan CL0454
InterPro IPR008197
PROSITE PDOC00026
SCOP 1fle
SUPERFAMILY 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[edit]

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[edit]

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]

Furthermore, transcription factor nuclear factor kappa B (NF-κB) is affected, leading to angiogenesis, cell proliferation, invasion and apoptosis.[2]

Biochemistry of WAP motifs[edit]

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

                          +---------------------+
                          |    +-----------+    |
                          |    |           |    |
        xxxxxxxCPxxxxxxxxxCxxxxCxxxxxCxxxxxCCxxxCxxxCxxxx
               |                     |      |       |
               |                     +--------------+
               |                            |
               +----------------------------+
        <------------------50-residues------------------>

'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.

References[edit]

  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. ^ a b 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

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External database links

This tab holds annotation information from the InterPro database.

InterPro entry 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].

Gene Ontology

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Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan Protease_inhib (CL0454), which has the following description:

This superfamily includes several families of toxins which seem to act as protease inuibitors.

The clan contains the following 2 members:

Kunitz_BPTI WAP

Alignments

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  Seed
(72)
Full
(1589)
Representative proteomes NCBI
(1565)
Meta
(1)
RP15
(219)
RP35
(260)
RP55
(462)
RP75
(826)
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  Seed
(72)
Full
(1589)
Representative proteomes NCBI
(1565)
Meta
(1)
RP15
(219)
RP35
(260)
RP55
(462)
RP75
(826)
Alignment:
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We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.

  Seed
(72)
Full
(1589)
Representative proteomes NCBI
(1565)
Meta
(1)
RP15
(219)
RP35
(260)
RP55
(462)
RP75
(826)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download   Download  
Gzipped Download   Download   Download   Download   Download   Download   Download   Download  

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.

Pfam alignments:

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Trees

This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

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Curation and family details

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Curation View help on the curation process

Seed source: Swissprot_feature_table
Previous IDs: wap;
Type: Domain
Author: Sonnhammer ELL
Number in seed: 72
Number in full: 1589
Average length of the domain: 44.60 aa
Average identity of full alignment: 36 %
Average coverage of the sequence by the domain: 19.27 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -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: 43
Family (HMM) version: 16
Download: download the raw HMM for this family

Species distribution

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Interactions

There is 1 interaction for this family. More...

Trypsin

Structures

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 5 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 seqence.

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