9GW9

Cryo-EM structure of Gephyrin E domain filament interface

Summary for 9GW9

• Entry DOI: 10.2210/pdb9gw9/pdb
• EMDB information: 51644
• Descriptor: Gephyrin (1 entity in total)
• Functional Keywords: dimer, filament, scaffolding, inhibitory synapse, protein binding
• Biological source: Rattus norvegicus (Norway rat)
• Total number of polymer chains: 3
• Total formula weight: 139921.06

Authors

Macha, A.,Gunkel, M.,Schwarz, G.,Behrmann, E.,Burdina, N. (deposition date: 2024-09-26, release date: 2025-10-08, Last modification date: 2026-04-22)

Primary citation

Macha, A.,Liebsch, F.,Bruckisch, E.H.W.,Burdina, N.,von Stulpnagel, I.,Benting, K.,Gunkel, M.,Behrmann, E.,Schwarz, G.
Gephyrin filaments represent the molecular basis of inhibitory postsynaptic densities.
Nat Commun, 16:8293-8293, 2025

PubMed Abstract: 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.

PubMed: 40957893
DOI: 10.1038/s41467-025-63748-w

Experimental method

ELECTRON MICROSCOPY (3.6 Å)