9B69

GluA2 flip Q in complex with TARPgamma2 at pH8, class12, structure of NTD

9B69 の概要

• エントリーDOI: 10.2210/pdb9b69/pdb
• 関連するPDBエントリー: 9B5Z 9B60 9B61 9B63 9B64 9B67
• EMDBエントリー: 44234 44244 44245 44248 44250
• 分子名称: Isoform Flip of Glutamate receptor 2, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (4 entities in total)
• 機能のキーワード: ampa receptor, ionotropic glutamate receptor, ion channel, auxiliary subunit, transport protein
• 由来する生物種: Rattus norvegicus (Norway rat)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 400713.06

構造登録者

Nakagawa, T.,Greger, I.H. (登録日: 2024-03-23, 公開日: 2024-07-31, 最終更新日: 2024-10-30)

主引用文献

Ivica, J.,Kejzar, N.,Ho, H.,Stockwell, I.,Kuchtiak, V.,Scrutton, A.M.,Nakagawa, T.,Greger, I.H.
Proton-triggered rearrangement of the AMPA receptor N-terminal domains impacts receptor kinetics and synaptic localization.
Nat.Struct.Mol.Biol., 31:1601-1613, 2024

PubMed Abstract: AMPA glutamate receptors (AMPARs) are ion channel tetramers that mediate the majority of fast excitatory synaptic transmission. They are composed of four subunits (GluA1-GluA4); the GluA2 subunit dominates AMPAR function throughout the forebrain. Its extracellular N-terminal domain (NTD) determines receptor localization at the synapse, ensuring reliable synaptic transmission and plasticity. This synaptic anchoring function requires a compact NTD tier, stabilized by a GluA2-specific NTD interface. Here we show that low pH conditions, which accompany synaptic activity, rupture this interface. All-atom molecular dynamics simulations reveal that protonation of an interfacial histidine residue (H208) centrally contributes to NTD rearrangement. Moreover, in stark contrast to their canonical compact arrangement at neutral pH, GluA2 cryo-electron microscopy structures exhibit a wide spectrum of NTD conformations under acidic conditions. We show that the consequences of this pH-dependent conformational control are twofold: rupture of the NTD tier slows recovery from desensitized states and increases receptor mobility at mouse hippocampal synapses. Therefore, a proton-triggered NTD switch will shape both AMPAR location and kinetics, thereby impacting synaptic signal transmission.

PubMed: 39138332
DOI: 10.1038/s41594-024-01369-5

実験手法

ELECTRON MICROSCOPY (3.69 Å)