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Structure paper

TitleStructural Bases of Desensitization in AMPA Receptor-Auxiliary Subunit Complexes.
Journal, issue, pagesNeuron, Vol. 94, Issue 3, Page 569-580.e5, Year 2017
Publish dateMay 3, 2017
AuthorsEdward C Twomey / Maria V Yelshanskaya / Robert A Grassucci / Joachim Frank / Alexander I Sobolevsky /
PubMed AbstractFast excitatory neurotransmission is mediated by AMPA-subtype ionotropic glutamate receptors (AMPARs). AMPARs, localized at post-synaptic densities, are regulated by transmembrane auxiliary subunits ...Fast excitatory neurotransmission is mediated by AMPA-subtype ionotropic glutamate receptors (AMPARs). AMPARs, localized at post-synaptic densities, are regulated by transmembrane auxiliary subunits that modulate AMPAR assembly, trafficking, gating, and pharmacology. Aberrancies in AMPAR-mediated signaling are associated with numerous neurological disorders. Here, we report cryo-EM structures of an AMPAR in complex with the auxiliary subunit GSG1L in the closed and desensitized states. GSG1L favors the AMPAR desensitized state, where channel closure is facilitated by profound structural rearrangements in the AMPAR extracellular domain, with ligand-binding domain dimers losing their local 2-fold rotational symmetry. Our structural and functional experiments suggest that AMPAR auxiliary subunits share a modular architecture and use a common transmembrane scaffold for distinct extracellular modules to differentially regulate AMPAR gating. By comparing the AMPAR-GSG1L complex structures, we map conformational changes accompanying AMPAR recovery from desensitization and reveal structural bases for regulation of synaptic transmission by auxiliary subunits.
External linksNeuron / PubMed:28472657 / PubMed Central
MethodsEM (single particle)
Resolution4.6 - 8.4 Å
Structure data

EMDB-8685, PDB-5vhw:
GluA2-0xGSG1L bound to ZK
Method: EM (single particle) / Resolution: 7.8 Å

EMDB-8686, PDB-5vhx:
GluA2-1xGSG1L bound to ZK
Method: EM (single particle) / Resolution: 8.3 Å

EMDB-8687, PDB-5vhy:
GluA2-2xGSG1L bound to ZK
Method: EM (single particle) / Resolution: 4.6 Å

EMDB-8688, PDB-5vhz:
GluA2-2xGSG1L bound to L-Quisqualate
Method: EM (single particle) / Resolution: 8.4 Å

Chemicals

ChemComp-ZK1:
{[7-morpholin-4-yl-2,3-dioxo-6-(trifluoromethyl)-3,4-dihydroquinoxalin-1(2H)-yl]methyl}phosphonic acid / antagonist, medication*YM

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-QUS:
(S)-2-AMINO-3-(3,5-DIOXO-[1,2,4]OXADIAZOLIDIN-2-YL)-PROPIONIC ACID / agonist*YM

Source
  • rattus norvegicus (Norway rat)
KeywordsTRANSPORT PROTEIN / Ion channel

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