Genetic,structural,and chemical insights into the dual function of GRASP55 in germ cell Golgi remodeling and JAM-C polarized localization during spermatogenesis

Spermatogenesis is a dynamic process that is regulated by adhesive interactions between germ and sertoli cells. germ cells express the junctional adhesion molecule-c (jam-c,encoded by jam3),which localizes to germ/sertoli cell contacts. jam-c is involved in germ cell polarity and acrosome formation. using a proteomic approach,we demonstrated that jam-c interacted with the golgi reassembly stacking protein of 55 kda (grasp55,encoded by gorasp2) in developing germ cells. generation and study of gorasp2-/-mice revealed that knock-out mice suffered from spermatogenesis defects. acrosome formation and polarized localization of jam-c in spermatids were altered in gorasp2-/-mice. in addition,golgi morphology of spermatocytes was disturbed in gorasp2-/-mice. crystal structures of grasp55 in complex with jam-c or jam-b revealed that grasp55 interacted via pdz-mediated interactions with jams and induced a conformational change in grasp55 with respect of its free conformation. an in silico pharmacophore approach identified a chemical compound called graspin that inhibited pdz-mediated interactions of grasp55 with jams. treatment of mice with graspin hampered the polarized localization of jam-c in spermatids,induced the premature release of spermatids and affected the golgi morphology of meiotic spermatocytes. © 2017 cartier-michaud et al.