Organization of the Human Gene Encoding the Epididymis-Specific EP2 Protein Variants and Its Relationship to Defensin Genes1

Abstract

The EP2 gene codes for at least nine message variants that are all specifically expressed in the epididymis. These variants putatively encode small secretory proteins that differ in their N- and C-termini, resulting in proteins that can have little or no sequence similarity to each other. We have isolated and sequenced the human EP2 gene to determine the molecular origin of these variants. The EP2 gene has two promoters, eight exons, and seven introns. Exons 3 and 6 encode protein sequences homologous to beta-defensins, a family of antimicrobial peptides. This sequence homology and the arrangement of promoters and defensin-encoding exons suggest that the EP2 gene originated from two ancestral beta-defensin genes arranged in tandem, each contributing a promoter and two exons encoding a leader sequence and a defensin peptide. The proposed evolutionary relationship between the EP2 gene and defensin genes is supported by the observation that the EP2 gene is located on chromosome 8p23 near the defensin gene cluster and is separated by 100 kilobases or less from DEFB2, the gene for beta-defensin-2. While the EP2 gene transcribes beta-defensin-like message variants, most of the known message variants code for nondefensin proteins or proteins containing only a partial defensin peptide sequence. We suggest that, during its evolution, the EP2 gene has acquired new functions that may be important for sperm maturation and/or storage in the epididymis.

Human β-defensins

“…This extension, rich in anionic residues, has no evident sequence similarity to other β-defensins [67,68]. Similar motifs are also found in the β-defensin-like family of HE2 peptides [65,82,85]. It was suggested that these long C-termini contribute to the decreased salt sensitivity of the antibacterial activity, as observed for β-defensin 118 [67].…”

“…The human gene encoding EP2 is located within the same section of chromosome 8 as several of the β-defensin genes [60,71]. Through splice variation, several transcripts of the EP2 gene (EP2A-EP2I) are generated in various regions of the human and chimpanzee epididymis [82][83][84]. Three of these variants, EP2C/D/E, share the cysteine motifs with β-defensins [82,83].…”

“…Through splice variation, several transcripts of the EP2 gene (EP2A-EP2I) are generated in various regions of the human and chimpanzee epididymis [82][83][84]. Three of these variants, EP2C/D/E, share the cysteine motifs with β-defensins [82,83]. The members of the EP2 family also share antibacterial properties with β-defensins [85,86].…”

Contribution of epididymal secretory proteins for spermatozoa maturation

“…ACE on sperm membrane is lost from the surface and discharged in the surrounding medium of the gametes Reproduced from Gatti et al (1999) with permission of the publisher. sage variants code for nondefensin proteins or proteins containing only a partial defensin peptide sequence (Fröhlich et al, 2001). Bin1b also exhibits structural characteristics in rats and antimicrobial activity similar to that of cationic antimicrobial peptides, i.e., betadefensins (Fan et al, 1999).…”

Innate immune responses of epididymal epithelial cells to Staphylococcus aureus infection

“…The epididymal epithelial cells, like other epithelial cells, express and secrete antimicrobial peptides and proteins, such as defensin, mucin, eppin, cationic antimicrobial protein 18, lipopolysaccharide binding protein, sperm antigen 11 [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25]. These defense effectors protect spermatozoa from invading pathogens * Corresponding author.…”