PLC vs PAWP

Fertilization signals Ca2+ oscillations occur and the resumption of meiosis in the egg (Runft et al., 2002; Wu et al., 2006). How sperm entry into the egg promotes these two events is not understood, and a topic of fierce debate.  Whereas many scientists agree that sperm release an egg activating factor after entry into the egg, the molecular identify of the activating factor is highly contested.  The debate focuses on two sperm-derived molecules in particular, PLCzeta (Saunders et al. 2002) and PAWP (Wu et al. 2007) .

A brief background on these two proteins…

PLCzeta: A phospholipase C, which cleaves the phospholipid PIP2 to generate IP3 and DAG.  PLCzeta shares sequence similarity with PLCdeta, although it lacks the PH domain that localizes PLCdelta to the inositol head group of PIP2.  

PAWP (Postacrosomal sheath WW domain-binding protein): a protein present in the postacrosomal sheath of sperm, a region that would be hidden until sperm are ready to fertilize.  This protein shares sequence homology to the N-terminal half of WW Binding Protein 2, while the C-terminal half is unique and rich in proline.

In order to determine how PLCzeta and PAWP may  contribute to fertilization, each protein has been examined for their ability to induce in Ca2+ oscillations or meiotic resumption: an ideal sperm factor should be able to induce both events in the egg.

In 2002, Saunders et al. demonstrated that PLCzeta triggered Ca2+ oscillations and claimed that this was the necessary sperm factor for fertilization to occur. In 2007, Wu et al. fulfilled the second requirement of demonstrating meiotic resumption when they utilized PAWP. However at this time, neither PAWP nor PLCzeta were assessed for both Ca2+ oscillations and meiotic resumption.

Recently, PAWP was assessed for Ca2+ oscillations by Aarabi and colleagues (2014). This study demonstrated that not only did PAWP cause Ca2+ oscillations, but that the WW domain PAWP interacts with is also important for Ca2+ oscillations. This was shown when they inhibited the WW domain and prevented Ca2+ oscillations.

Currently, we know that both PAWP and PLCzeta can trigger Ca2+ oscillations and that removal of either protein from sperm extracts precludes induction of Ca2+ oscillations. However, it is still unclear if PLCzeta induces meiotic resumption. Nonetheless, PLCzeta specificity for the PIP2 hydrolysis necessary for Ca2+ elevation in the cell makes PLCzeta a strong candidate for the sperm factor (Nomikos et al. 2015). Since PAWP also causes Ca2+ oscillations, question remains on how PAWP induces these oscillations. A known route for Ca2+ elevation is through PLCzeta’s hydrolysis of PIP2 (Nomikos et al., 2011). Thus, another question to pose would be if PAWP interacts with PLCzeta.

Further insight into PLCzeta and PAWP is required to determine if both factors are required. The two factors can may have additive effects or perhaps one factor dominates the other and one acts as back up, but this remains unclear.

Post by Wase Tembo and Anne Carlson