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Genetic, structural, and chemical insights into the dual function of GRASP55 in germ cell Golgi remodeling and JAM-C polarized localization during spermatogenesis.
- Source :
-
PLoS genetics [PLoS Genet] 2017 Jun 15; Vol. 13 (6), pp. e1006803. Date of Electronic Publication: 2017 Jun 15 (Print Publication: 2017). - Publication Year :
- 2017
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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.
- Subjects :
- Animals
Binding Sites
Carrier Proteins chemistry
Carrier Proteins genetics
Cells, Cultured
Golgi Apparatus ultrastructure
Intracellular Signaling Peptides and Proteins
Male
Membrane Proteins chemistry
Membrane Proteins genetics
Mice
Mice, Inbred C57BL
Protein Binding
Protein Transport
Spermatogonia cytology
Carrier Proteins metabolism
Cell Adhesion Molecules metabolism
Golgi Apparatus metabolism
Immunoglobulins metabolism
Membrane Proteins metabolism
Spermatogenesis
Spermatogonia metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1553-7404
- Volume :
- 13
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- PLoS genetics
- Publication Type :
- Academic Journal
- Accession number :
- 28617811
- Full Text :
- https://doi.org/10.1371/journal.pgen.1006803