Universität zu Köln

Gruenewald, Nora, Jan, Audric ORCID: 0000-0001-5006-4190, Salvatico, Charlotte, Kress, Vanessa, Renner, Marianne ORCID: 0000-0002-8727-6581, Triller, Antoine, Specht, Christian G. and Schwarz, Guenter ORCID: 0000-0002-2118-9338 (2018). Sequences Flanking the Gephyrin-Binding Site of GlyR beta Tune Receptor Stabilization at Synapses. eNeuro, 5 (1). WASHINGTON: SOC NEUROSCIENCE. ISSN 2373-2822

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Abstract

The efficacy of synaptic transmission is determined by the number of neurotransmitter receptors at synapses. Their recruitment depends upon the availability of postsynaptic scaffolding molecules that interact with specific binding sequences of the receptor. At inhibitory synapses, gephyrin is the major scaffold protein that mediates the accumulation of heteromeric glycine receptors (GlyRs) via the cytoplasmic loop in the beta-subunit (beta-loop). This binding involves high- and low-affinity interactions, but the molecular mechanism of this bimodal binding and its implication in GlyR stabilization at synapses remain unknown. We have approached this question using a combination of quantitative biochemical tools and high-density single molecule tracking in cultured rat spinal cord neurons. The high-affinity binding site could be identified and was shown to rely on the formation of a 310-helix C-terminal to the beta-loop core gephyrin-binding motif. This site plays a structural role in shaping the core motif and represents the major contributor to the synaptic confinement of GlyRs by gephyrin. The N-terminal flanking sequence promotes lower affinity interactions by occupying newly identified binding sites on gephyrin. Despite its low affinity, this binding site plays a modulatory role in tuning the mobility of the receptor. Together, the GlyR beta-loop sequences flanking the core-binding site differentially regulate the affinity of the receptor for gephyrin and its trapping at synapses. Our experimental approach thus bridges the gap between thermodynamic aspects of receptor-scaffold interactions and functional receptor stabilization at synapses in living cells.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Gruenewald, Nora UNSPECIFIED UNSPECIFIED UNSPECIFIED Jan, Audric UNSPECIFIED orcid.org/0000-0001-5006-4190 UNSPECIFIED Salvatico, Charlotte UNSPECIFIED UNSPECIFIED UNSPECIFIED Kress, Vanessa UNSPECIFIED UNSPECIFIED UNSPECIFIED Renner, Marianne UNSPECIFIED orcid.org/0000-0002-8727-6581 UNSPECIFIED Triller, Antoine UNSPECIFIED UNSPECIFIED UNSPECIFIED Specht, Christian G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schwarz, Guenter UNSPECIFIED orcid.org/0000-0002-2118-9338 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-203103
DOI:	10.1523/ENEURO.0042-17.2018
Journal or Publication Title:	eNeuro
Volume:	5
Number:	1
Date:	2018
Publisher:	SOC NEUROSCIENCE
Place of Publication:	WASHINGTON
ISSN:	2373-2822
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Chemistry > Institute of Biochemistry
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language GAMMA-AMINOBUTYRIC-ACID; GLYCINE RECEPTOR; ACETYLCHOLINE-RECEPTOR; INHIBITORY SYNAPSES; CRYSTAL-STRUCTURES; PROTEIN GEPHYRIN; MOLECULAR-BASIS; ALPHA-HELICES; DIFFUSION; MEMBRANE Multiple languages Neurosciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/20310