1. Genetic, structural, and chemical insights into the dual function of GRASP55 in germ cell Golgi remodeling and JAM-C polarized localization during spermatogenesis.
- Author
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Cartier-Michaud, Amandine, Bailly, Anne-Laure, Betzi, Stéphane, Shi, Xiaoli, Lissitzky, Jean-Claude, Zarubica, Ana, Sergé, Arnauld, Roche, Philippe, Lugari, Adrien, Hamon, Véronique, Bardin, Florence, Derviaux, Carine, Lembo, Frédérique, Audebert, Stéphane, Marchetto, Sylvie, Durand, Bénédicte, Borg, Jean-Paul, Shi, Ning, Morelli, Xavier, and Aurrand-Lions, Michel
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GENETICS of spermatogenesis ,GERM cells ,GOLGI apparatus ,ACROSOME reaction ,MEIOTIC drive ,PHYSIOLOGY - 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. [ABSTRACT FROM AUTHOR]- Published
- 2017
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