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.

译文

精子发生是一个动态过程,由生殖细胞和支持细胞之间的粘附相互作用调节。生殖细胞表达连接粘附分子-C (JAM-C,由Jam3编码),其定位于生殖/支持细胞接触。JAM-C参与生殖细胞极性和胚体形成。使用蛋白质组学方法,我们证明了JAM-C在发育中的生殖细胞中与55 kDa的高尔基重组堆积蛋白 (GRASP55,由Gorasp2编码) 相互作用。Gorasp2-/-小鼠的产生和研究表明,敲除小鼠患有精子发生缺陷。在Gorasp2-/-小鼠中,精子细胞中JAM-C的顶体形成和极化定位发生了改变。此外,Gorasp2-/-小鼠的精母细胞高尔基体形态受到干扰。GRASP55与JAM-C或JAM-B配合物的晶体结构表明,GRASP55通过PDZ介导的与JAMs的相互作用,并在其自由构象方面引起GRASP55的构象变化。计算机药效团方法确定了一种称为Graspin的化合物,该化合物抑制了PDZ介导的GRASP55与果酱的相互作用。用Graspin处理小鼠会阻碍JAM-C在精子中的极化定位,诱导精子的过早释放并影响减数分裂精母细胞的高尔基体形态。

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