Abstract
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.
Highlights
Members of the Junctional Adhesion Molecular family exhibit a similar structure with two extracellular immunoglobulin domains, a single transmembrane region and a C-terminal PSD-95/Discs Large/ZO-1 (PDZ)-binding motif
We previously demonstrated that the Junctional Adhesion Molecule-C (JAM-C) plays a crucial role in establishing spermatids polarity
The present study demonstrated that the C-terminal cytosolic region of JAM-C interacted with the Golgi reassembly stacking protein of 55 kDa (GRASP55) encoded by Gorasp2 and that spermatogenesis was impaired in Gorasp2-deficient mice
Summary
Members of the Junctional Adhesion Molecular family exhibit a similar structure with two extracellular immunoglobulin domains, a single transmembrane region and a C-terminal PSD-95/Discs Large/ZO-1 (PDZ)-binding motif. Three of these proteins are highly similar: JAM-A, JAM-B and JAM-C [1]. Spermatogenesis involves adhesive interactions between developing germ and Sertoli cells [7] and is a continuous process that requires 34.5 days in mice. Germ cells express JAM-C which participates to spermatogenesis via interaction with JAM-B during post-meiotic maturation of spermatids [6, 11]. Junctional plaques are specialized adhesion structures that anchor germ cells to Sertoli cells and provide spermatids with polarization cues, including JAM-C-mediated polarity signals. The present study used a combination of proteomic and genetic techniques with structural biochemistry and structure-based drug design approaches to investigate these mechanisms
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