Sperm–egg binding (left) is lost when ACE GPIase activity is missing (right).

KONDOH/MACMILLAN

A target of blood pressure–lowering drugs harbors the unexpected ability to release GPI-anchored proteins. Gen Kondoh (Kyoto University, Kyoto, Japan), Junji Takeda (Osaka University, Osaka, Japan), and colleagues reveal that this enzyme, ACE, is both a peptidase and GPIase in one multifunctional package.ACE's peptidase activity is well studied—it cleaves and activates angiotensin, which up-regulates blood pressure through hormonal changes. But Kondoh did not expect to find ACE in his screen for proteins that release GPI-anchored proteins from the cell surface.

GPI deficiencies cause severe problems in fertility and development. GPI also links the prion protein to membranes. But the activities that release these linkages were not well-known. Now, Kondoh shows that a region of ACE distinct from its peptidase domain has this ability. Soluble prion protein protects against scrapie, so ACE, especially a peptidase-inactive form, may be a useful disease treatment.

As ACE was found in a mouse testicular preparation, the group examined sperm lacking the ACE GPIase activity. The mutant sperm were infertile and unable to release several GPI-linked proteins from their surface.

Anchored proteins were partly protected from ACE cleavage if they were in lipid rafts. By keeping GPI-linked fertilization factors in rafts, their release could be delayed until the raft disruption that occurs during capacitation.

Reference:

Kondoh, G., et al. 2005. Nat. Med. doi:10.1038/nm1179