title: A conformational switch in collybistin determines the differentiation of inhibitory postsynapses.
abstract: The formation of neuronal synapses and the dynamic regulation of their efficacy depend on the assembly of the postsynaptic neurotransmitter receptor apparatus. Receptor recruitment to inhibitory GABAergic and glycinergic synapses is controlled by the scaffold protein gephyrin and the adaptor protein collybistin. We derived new insights into the structure of collybistin and used these to design biochemical, cell biological, and genetic analyses of collybistin function. Our data define a collybistin-based protein interaction network that controls the gephyrin content of inhibitory postsynapses. Within this network, collybistin can adopt open/active and closed/inactive conformations to act as a switchable adaptor that links gephyrin to plasma membrane phosphoinositides. This function of collybistin is regulated by binding of the adhesion protein neuroligin-2, which stabilizes the open/active conformation of collybistin at the postsynaptic plasma membrane by competing with an intramolecular interaction in collybistin that favors the closed/inactive conformation. By linking trans-synaptic neuroligin-dependent adhesion and phosphoinositide signaling with gephyrin recruitment, the collybistin-based regulatory switch mechanism represents an integrating regulatory node in the formation and function of inhibitory postsynapses.
authors.affiliation: Department of Molecular Neurobiology, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: Tolga
authors.initials: T
authors.lastname: Soykan
authors.affiliation: Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Schneeberger
authors.affiliation: European Molecular Biology Laboratory, Hamburg Outstation, Hamburg, Germany Centre for Bioinformatics, University of Hamburg, Hamburg, Germany.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Tria
authors.affiliation: Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Buechner
authors.affiliation: Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Bader
authors.affiliation: European Molecular Biology Laboratory, Hamburg Outstation, Hamburg, Germany.
authors.forename: Dmitri
authors.initials: D
authors.lastname: Svergun
authors.affiliation: Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Tessmer
authors.affiliation: Department of Molecular Neurobiology, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: Alexandros
authors.initials: A
authors.lastname: Poulopoulos
authors.affiliation: Department of Molecular Neurobiology, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: Theofilos
authors.initials: T
authors.lastname: Papadopoulos
authors.affiliation: Department of Molecular Neurobiology, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Varoqueaux
authors.affiliation: Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany hermann.schindelin@virchow.uni-wuerzburg.de brose@em.mpg.de.
authors.forename: Hermann
authors.initials: H
authors.lastname: Schindelin
authors.affiliation: Department of Molecular Neurobiology, Max Planck Institute of Experimental Medicine, Göttingen, Germany hermann.schindelin@virchow.uni-wuerzburg.de brose@em.mpg.de.
authors.forename: Nils
authors.initials: N
authors.lastname: Brose
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D002352:Carrier Proteins / Q000032:analysis*; D002462:Cell Membrane / Q000737:chemistry; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D008565:Membrane Proteins / Q000032:analysis*; D051379:Mice; D018625:Microscopy, Atomic Force; D008954:Models, Biological; D008958:Models, Molecular; D011487:Protein Conformation; D064067:Rho Guanine Nucleotide Exchange Factors / Q000737:chemistry* / Q000378:metabolism*; D053838:Scattering, Small Angle; D013569:Synapses / Q000737:chemistry* / Q000502:physiology*
chemical_list: C577403:Arhgef9 protein, mouse; D002352:Carrier Proteins; D008565:Membrane Proteins; D064067:Rho Guanine Nucleotide Exchange Factors; C073441:gephyrin
keywords: autoinhibition; conformational activation; gephyrin; inhibitory synapse; neuroligin‐2
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