The structure and function relationship of sperm PLC-zeta

In 2002, sperm-specific phospholipase C zeta (PLCζ) was discovered and through these twenty years, it has been established as the predominant sperm oocyte-activating factor. PLCζ cRNA expression or direct protein microinjection into mammalian oocytes triggers calcium (Ca2+) oscillations indistinguishable from those observed at fertilization. The imperative role of PLCζ in oocyte activation is revealed by the vast number of human mutations throughout the PLCζ gene that have been identified and directly linked with certain forms of male infertility due to oocyte activation deficiency. PLCζ is the smallest PLC in size, comprising four N-terminal EF-hand domains, followed by X and Y catalytic domains, which are separated by the XY linker, and ending with a C-terminal C2 domain. The EF-hands are responsible for the high Ca2+ sensitivity of PLCζ. The X and Y catalytic domains are responsible for the catalysis of the phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] substrate to produce the Ca2+-mobilising messenger, inositol 1,4,5-trisphosphate (IP3), while the XY linker plays multiple roles in the unique mode of PLCζ action. Finally, the C2 domain has been proposed to facilitate the anchoring of PLCζ to intracellular vesicles through its direct interactions with specific phosphoinositides. This review discusses recent advances in the structure and function relationship of PLCζ and the potential binding partners of this important sperm-specific protein in the sperm and oocyte. The unravelling of all the remaining hidden secrets of sperm PLCζ should help us to understand the precise mechanism of fertilization, as well as enabling the diagnosis and treatment of currently unknown forms of PLCζ-linked human infertility.