Fertilin is a
protein initially identified in guinea pig spermatozoa; it is the prototype of a larger family of conserved,
proteins designated as a
disintegrin and a
metalloproteinase (ADAM). These heterodimers which consist of alpha and beta subunits, containing
metalloproteinase-like and
disintegrin-like domains, appear to play a role in mammalian fertilization.
Peptides derived from the
disintegrin domains of two ADAMs,
fertilin and cyritestin, interfere with gamete adhesion and sperm-egg membrane fusion in non-human species. It has been suggested that
fertilin-beta binds to an oolemmal
integrin, and it is proposed that the tripeptide FEE (
Phe-Glu-Glu) is the
integrin recognition sequence in human
fertilin-beta. We evaluated whether
fertilin beta plays a role in human fertilization by studying the effects of a linear octapeptide containing the FEE sequence, SFEECDLP, and a scrambled octapeptide with the same
amino acids, SFPCEDEL, on the incorporation of human spermatozoa by human
zona-free eggs. The effects of G4120, a potent RGD-containing (
Arg-Gly-Asp)
thioether-bridged
cyclic peptide which blocks both
fibronectin and
vitronectin receptors, and the relationship between FEE- and
RGD-receptor interactions on sperm-egg interactions were also studied. The FEE-containing
peptide, but not the scrampled
peptide, inhibited sperm adhesion to oocytes and their penetration, over the range 1-5 microM. The inhibition induced by SFEECDLP was reversible and occurred only in the presence of
peptide itself. The G4120
peptide exhibited 10-fold less inhibitory effects on sperm adhesion and penetration than did SFEECDLP. When combined, SFEECDLP and G4120 exhibited strong inhibition of both adhesion and penetration at concentrations that individually had been ineffective, suggesting co-operation between the two receptor-
ligand interactions during fertilization. We propose that a
fertilin-like molecule is functionally active on human spermatozoa and that its interaction with an oolemmal
integrin receptor plays a role in fertilization in humans.