PCSK4-null sperm display enhanced protein tyrosine phosphorylation and ADAM2 proteolytic processing during in vitro capacitation

Objective To study the molecular basis for the accelerated capacitation rate in PCSK4-null sperm. Design Comparative and controlled experimental research study. Setting Academic medical institute. Animal(s) Male mice C57BL/6J wild-type or null congenics for the Pcsk4 allele. Intervention(s) Cauda and epididymal sperm were capacitated for varying times. Main Outcome Measure(s) Differences in sperm protein tyrosine phosphorylation and proteolytic processing of sperm-egg ligands ADAM2 and ADAM3. Result(s) The PCSK4-null sperm proteins are hyper–tyrosine phosphorylated during capacitation. This hyperphosphorylation is dependent on protein kinase A (PKA), albumin, and calcium. There is also more ADAM2 proteolytic processing from a 46-kDa form of ADAM2 to a 27-kDa form in PCSK4-null sperm than in wild-type sperm. This processing is dependent on cholesterol efflux. Conclusion(s) Lack of PCSK4 is associated with quantitative changes in the phosphorylation and proteolysis of sperm proteins during capacitation; therefore, alterations in signal transduction and proteolytic processing during capacitation may underlie the fertilization incompetence of PCSK4-null sperm. More investigation is needed to determine how and to what extent these changes might contribute to the loss of fertilizing ability of PCSK4-null sperm.