Universität zu Köln

Macha, Arthur ORCID: 0009-0007-1798-4412, Liebsch, Filip ORCID: 0000-0002-0955-8065, Bruckisch, Emanuel H. W. ORCID: 0000-0003-2551-5919, Burdina, Nele ORCID: 0009-0000-3200-918X, von Stülpnagel, Imke ORCID: 0009-0001-0819-5784, Benting, Konrad ORCID: 0009-0000-5222-4282, Gunkel, Monika ORCID: 0000-0001-9433-6127, Behrmann, Elmar ORCID: 0000-0001-6794-3669 and Schwarz, Guenter ORCID: 0000-0002-2118-9338 (2025). Gephyrin filaments represent the molecular basis of inhibitory postsynaptic densities. Nature Communications, 16 (1). Springer Nature. ISSN 2041-1723

PDF s41467-025-63748-w.pdf Bereitstellung unter der CC-Lizenz: Creative Commons Attribution. Download (7MB)

Abstract

[Artikel-Nr.: 8293] The multifunctional protein gephyrin clusters inhibitory receptors at the postsynaptic membrane in the CNS. Gephyrin has been proposed to form the inhibitory postsynaptic density by liquid-liquid phase separation, involving a complex interplay between receptor binding and oligomerization via its conserved G- and E-domains. Here we show by single particle cryo-EM analysis that dimerization promotes the formation of gephyrin filaments in which two E-domain dimers are linked by Z-shaped interfaces formed between two subdomains II (SDII) of adjacent dimers. Deletion of SDII, introduction of two epilepsy-causing pathogenic variants, or neutralization of an opposing charge in the interface abolish the formation of filaments, in vitro phase separation, and synaptic receptor clustering in hippocampal neurons. In conclusion, this work identifies gephyrin E-domain filaments as the structural foundation underlying gephyrin both phase separation and receptor clustering at inhibitory postsynaptic densities.

Item Type:	Article
Creators:	Creators Email ORCID ORCID Put Code Macha, Arthur UNSPECIFIED https://orcid.org/0009-0007-1798-4412 UNSPECIFIED Liebsch, Filip UNSPECIFIED https://orcid.org/0000-0002-0955-8065 UNSPECIFIED Bruckisch, Emanuel H. W. UNSPECIFIED https://orcid.org/0000-0003-2551-5919 UNSPECIFIED Burdina, Nele UNSPECIFIED https://orcid.org/0009-0000-3200-918X UNSPECIFIED von Stülpnagel, Imke UNSPECIFIED https://orcid.org/0009-0001-0819-5784 UNSPECIFIED Benting, Konrad UNSPECIFIED https://orcid.org/0009-0000-5222-4282 UNSPECIFIED Gunkel, Monika UNSPECIFIED https://orcid.org/0000-0001-9433-6127 UNSPECIFIED Behrmann, Elmar UNSPECIFIED https://orcid.org/0000-0001-6794-3669 UNSPECIFIED Schwarz, Guenter UNSPECIFIED https://orcid.org/0000-0002-2118-9338 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-806362
Identification Number:	10.1038/s41467-025-63748-w
Journal or Publication Title:	Nature Communications
Volume:	16
Number:	1
Number of Pages:	14
Date:	16 September 2025
Publisher:	Springer Nature
ISSN:	2041-1723
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences Faculty of Medicine
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Chemistry > Institute of Biochemistry Zentrum für Molekulare Medizin
Subjects:	Life sciences Medical sciences Medicine
['eprint_fieldname_oa_funders' not defined]:	Publikationsfonds UzK
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/80636