Molecular Basis of Mammalian Egg-Sperm Interaction

Objective

At the dawn of the 21st century, our knowledge of the molecular mechanism of mammalian
fertilization remains very limited. Different lines of evidence indicate that initial gamete recognition
depends on interaction between a few distinct proteins on sperm and ZP3, a major component of the
extracellular coat of oocytes, the zona pellucida (ZP). On the other hand, recent findings suggest an
alternative mechanism in which cleavage of another ZP subunit, ZP2, regulates binding of gametes
by altering the global structure of the ZP. Progress in the field has been hindered by the paucity and
heterogeneity of native egg-sperm recognition proteins, so that novel approaches are needed to
reconcile all available data into a single consistent model of fertilization. Following our recent
determination of the structure of the most conserved domain of sperm receptor ZP3 by X-ray
crystallography, we will conclusively establish the basis of mammalian gamete recognition by
performing structural studies of homogeneous, biologically active recombinant proteins. First, we
will combine crystallographic studies of isolated ZP subunits with electron microscopy analysis of
their filaments to build a structural model of the ZP. Second, structures of key egg-sperm
recognition protein complexes will be determined. Third, we will investigate how proteolysis of
ZP2 triggers overall conformational changes of the ZP upon gamete fusion. Together with
functional analysis of mutant proteins, these studies will provide atomic resolution snapshots of the
most crucial step in the beginning of a new life, directly visualizing molecular determinants
responsible for species-restricted gamete interaction at fertilization. The progressive decrease of
births in the Western world and inadequacy of current contraceptive methods in developing
countries underscore an urgent need for a modern approach to reproductive welfare. This research
will not only shed light on a truly fundamental biological problem, but also constitute a solid
foundation for the reproductive medicine of the future.

Fields of science

Funding Scheme

ERC-SG - ERC Starting Grant

Host institution

KAROLINSKA INSTITUTET

EU contribution

€ 1 499 281,60

Address

Nobels Vag 5
17177 Stockholm
Sweden

Region

Östra Sverige Stockholm Stockholms län

Activity type

Higher or Secondary Education Establishments

Administrative Contact

Thomas Tinglöv (Mr.)

Principal investigator

Luca Vincenzo Luigi Jovine (Dr.)

Links

Contact the organisation Website

Total cost

No data

Beneficiaries (1)