WHY DID THE SPERM CROSS THE CUMULUS - TO GET TO THE OOCYTE - FUNCTIONS OF THE SPERM SURFACE-PROTEINS PH-20 AND FERTILIN IN ARRIVING AT, ANDFUSING WITH, THE EGG

The sperm surface has an active role in the events of fertilization. T he definition of the sperm surface in both its composition and domain organization begins during spermatogenesis and continues until the mom ent of sperm-egg fusion. Alterations of the surface proceed as a resul t of internal programming and environmental cues from both the male an d female reproductive tracts, including interactions with the egg itse lf. We have investigated the sperm surface to understand its domain or ganization and the ongoing changes in this organization as well as the role of specific surface proteins in fertilization. Much of our resea rch has concentrated on two surface proteins: PH-20 and fertilin. PH-2 0 is a single-chain protein, anchored in the membrane via a glycosyl p hosphatidylinositol (GPI) anchor. The N-terminal domain of the molecul e has a hyaluronidase activity. The hyaluronidase activity of PH-20 on the sperm plasma membrane enables sperm to penetrate the layer of cum ulus cells surrounding the oocyte. PH-20 has a second function, unrela ted to its hyaluronidase activity, in the binding of acrosome-reacted sperm to the zona pellucida (secondary sperm-zona binding). The fertil in molecule is an alpha, beta heterodimer whose two subunits are close ly related transmembrane proteins. Fertilin beta has a disintegrin dom ain that has high sequence homology with the snake disintegrins, a kno wn class of soluble integrin ligands. The binding site of the beta dis integrin domain functions to bind sperm to the egg plasma membrane via a mechanism that leads to sperm-egg fusion. The precursor of fertilin alpha, made in the testis, has an active metalloprotease site that co uld function in spermatogenesis. This metalloprotease domain is remove d by proteolytic processing in the testis. Mature fertilin alpha on sp erm also has a hydrophobic, putative ''fusion peptide'' that may promo te the process of lipid bilayer fusion between sperm and egg plasma me mbranes. Fertilin alpha and beta are the first identified members of a new gene family of transmembrane proteins, the ADAM family, so called because they contain A Disintegrin And Metalloprotease domain. Many d istinct ADAMs have now been found in diverse tissues and species (Dros ophila to human) and are proposed to have a variety of functions in de velopment and the adult. In addition to fertilin, other ADAMs are also present on the sperm plasma membrane and may participate with fertili n in sperm-egg fusion.