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Crystal Structure of GRASP55 GRASP domain in complex with JAM-B C-terminus
Structural highlights
FunctionGORS2_MOUSE Plays a role in assembly and membrane stacking of the Golgi cisternae, and in the process by which Golgi stacks reform after mitotic breakdown. May regulate the intracellular transport and presentation of a defined set of transmembrane proteins, such as transmembrane TGFA.[1] Publication Abstract from PubMedSpermatogenesis 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. Genetic, structural, and chemical insights into the dual function of GRASP55 in germ cell Golgi remodeling and JAM-C polarized localization during spermatogenesis.,Cartier-Michaud A, Bailly AL, Betzi S, Shi X, Lissitzky JC, Zarubica A, Serge A, Roche P, Lugari A, Hamon V, Bardin F, Derviaux C, Lembo F, Audebert S, Marchetto S, Durand B, Borg JP, Shi N, Morelli X, Aurrand-Lions M PLoS Genet. 2017 Jun 15;13(6):e1006803. doi: 10.1371/journal.pgen.1006803., eCollection 2017 Jun. PMID:28617811[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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