7CQF

Crystal structure of PSD-95 PDZ3 fused with ADAM22 C-terminal peptide

7CQF の概要

• エントリーDOI: 10.2210/pdb7cqf/pdb
• 分子名称: Disks large homolog 4,Disintegrin and metalloproteinase domain-containing protein 22, CHLORIDE ION, CHOLINE ION, ... (5 entities in total)
• 機能のキーワード: scaffold protein, membrane receptor, signaling protein
• 由来する生物種: Rattus norvegicus (Rat); 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 16834.29

構造登録者

Yamagata, A.,Fukai, S. (登録日: 2020-08-10, 公開日: 2021-01-06, 最終更新日: 2023-11-29)

主引用文献

Fukata, Y.,Chen, X.,Chiken, S.,Hirano, Y.,Yamagata, A.,Inahashi, H.,Sanbo, M.,Sano, H.,Goto, T.,Hirabayashi, M.,Kornau, H.C.,Pruss, H.,Nambu, A.,Fukai, S.,Nicoll, R.A.,Fukata, M.
LGI1-ADAM22-MAGUK configures transsynaptic nanoalignment for synaptic transmission and epilepsy prevention.
Proc.Natl.Acad.Sci.USA, 118:-, 2021

PubMed Abstract: Physiological functioning and homeostasis of the brain rely on finely tuned synaptic transmission, which involves nanoscale alignment between presynaptic neurotransmitter-release machinery and postsynaptic receptors. However, the molecular identity and physiological significance of transsynaptic nanoalignment remain incompletely understood. Here, we report that epilepsy gene products, a secreted protein LGI1 and its receptor ADAM22, govern transsynaptic nanoalignment to prevent epilepsy. We found that LGI1-ADAM22 instructs PSD-95 family membrane-associated guanylate kinases (MAGUKs) to organize transsynaptic protein networks, including NMDA/AMPA receptors, Kv channels, and LRRTM4-Neurexin adhesion molecules. knock-in mice devoid of the ADAM22-MAGUK interaction display lethal epilepsy of hippocampal origin, representing the mouse model for ADAM22-related epileptic encephalopathy. This model shows less-condensed PSD-95 nanodomains, disordered transsynaptic nanoalignment, and decreased excitatory synaptic transmission in the hippocampus. Strikingly, without ADAM22 binding, PSD-95 cannot potentiate AMPA receptor-mediated synaptic transmission. Furthermore, forced coexpression of ADAM22 and PSD-95 reconstitutes nano-condensates in nonneuronal cells. Collectively, this study reveals LGI1-ADAM22-MAGUK as an essential component of transsynaptic nanoarchitecture for precise synaptic transmission and epilepsy prevention.

PubMed: 33397806
DOI: 10.1073/pnas.2022580118

実験手法

X-RAY DIFFRACTION (1.8 Å)