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TitleGephyrin filaments represent the molecular basis of inhibitory postsynaptic densities.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 8293, Year 2025
Publish dateSep 16, 2025
AuthorsArthur Macha / Filip Liebsch / Emanuel H W Bruckisch / Nele Burdina / Imke von Stülpnagel / Konrad Benting / Monika Gunkel / Elmar Behrmann / Guenter Schwarz /
PubMed AbstractThe 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 ...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.
External linksNat Commun / PubMed:40957893 / PubMed Central
MethodsEM (single particle)
Resolution3.1 - 3.6 Å
Structure data

51644

9gw9

EMDB-51644, PDB-9gw9:
Cryo-EM structure of Gephyrin E domain filament interface
Method: EM (single particle) / Resolution: 3.6 Å

EMDB-54820: Gephyrin E domain dimer G375D variant
Method: EM (single particle) / Resolution: 3.4 Å

EMDB-54821: Gephyrin E domain dimer D422N variant
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-54824: Gephyrin E domain dimer R379D variant
Method: EM (single particle) / Resolution: 3.5 Å

Source
  • rattus norvegicus (Norway rat)
KeywordsPROTEIN BINDING / Dimer / filament / scaffolding / inhibitory synapse

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