Sperm and eggs

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  • Published: Dec 15, 2008
  • Author: David Bradley
  • Channels: X-ray Spectrometry
thumbnail image: Sperm and eggs

Scientists at the Karolinska Institute in Sweden have obtained the first crystal structure of ZP3, a protein essential for the interaction between the mammalian egg coat and sperm. The work could eventually lead to improved contraceptives and perhaps has implications for fertility studies.

Traditionally, mammalian life starts with fertilization, the coalescence of genetic material. The critical step is the species-specific recognition between the two agents, egg and sperm. Karolinska's Luca Jovine explains that the receptors for sperm, proteins ZP3 and ZP2, have a common sequence that allows them to form a matrix of filaments, the so-called zona pellucida that completely surrounds the egg.

Like their counterparts in the vitelline envelope of non-mammalian eggs, the ZP3 and ZP2 receptors, and many other secreted eukaryotic proteins, polymerize using a "zona pellucida (ZP) domain" module, the researchers explain. Mice lacking either of the corresponding genes produce eggs without a zona pellucida and are completely infertile.

Now, Jovine and his colleagues in The Protein Crystallography Unit have determined the structure of the most conserved part of this building block, the ZP-N domain. They have found that it has an immunoglobulin-like fold and represents a new immunoglobulin superfamily subtype.

"ZP3 was identified almost 30 years ago," says Jovine, "but obtaining structural information on this key reproductive protein has been technically challenging due to its high heterogeneity."

Because the zona pellucida is essential for natural fertilization in mammals, the team hoped that their crystal structure of this region of ZP3, which is involved in its ability to polymerize, could help explain cases of human infertility, as well as lead to the development of novel targeted, non-hormonal contraceptives.

"Mammalian fertilization involves a highly complex series of events," adds Jovine, "Our findings pave the way for future investigations into this fascinating subject by providing a first snapshot of the beginning of life at atomic resolution."

Until now, researchers had not obtained an atomic-resolution structure of a ZP domain protein. Moreover, structural information for any conserved vertebrate protein essential to fertilization and directly involved in egg?sperm binding was entirely lacking. Jovine's team has now filled that gap with their 2.3 Å structure of the ZP-N fragment of mouse primary sperm receptor ZP3.

They explain, in a recent issue of the journal Nature, that, "The ZP-N fold defines a new immunoglobulin superfamily subtype with a beta-sheet extension characterized by an E' strand and an invariant tyrosine residue implicated in polymerization." This work, they say, supports the existence of ZP-N repeats within the N-terminal region of ZP2 and other vertebrate zona pellucida/vitelline envelope proteins and so has implications for the coat architecture of the egg.

The research also points to how multiple sperm entry, polyspermy, is normally blocked and could have unexpected implications for understanding the molecular features involved in speciation among vertebrates.
"We noticed a similarity between some molecular features that were shown to be involved in speciation in invertebrates and the structure of secondary sperm receptor ZP2," Jovine told SpectroscopyNOW, "Whether this is functionally meaningful also in vertebrates (and particularly mammals) remains entirely to be seen."

The team points out that ZP-N domains are found in many other extracellular proteins wholly unrelated to fertilization. The research could thus play a role in understanding human diseases such as non-syndromic deafness, renal and vascular disorders, and cancer. In their Nature paper, the team provides an example of how this structural information could be used to understand the molecular basis of some of these disorders.

Luca Jovine

Jovine, unscrambling egg receptors
Structure of the sperm receptor ZP3, a protein essential for egg-sperm interaction at fertilization. Credit Luca Jovine, Karolinska Institute
Receptive egg

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