7CQF
Crystal structure of PSD-95 PDZ3 fused with ADAM22 C-terminal peptide
Summary for 7CQF
| Entry DOI | 10.2210/pdb7cqf/pdb |
| Descriptor | Disks large homolog 4,Disintegrin and metalloproteinase domain-containing protein 22, CHLORIDE ION, CHOLINE ION, ... (5 entities in total) |
| Functional Keywords | scaffold protein, membrane receptor, signaling protein |
| Biological source | Rattus norvegicus (Rat) More |
| Total number of polymer chains | 1 |
| Total formula weight | 16834.29 |
| Authors | Yamagata, A.,Fukai, S. (deposition date: 2020-08-10, release date: 2021-01-06, Last modification date: 2023-11-29) |
| Primary citation | 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 Cited by 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: 33397806DOI: 10.1073/pnas.2022580118 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.8 Å) |
Structure validation
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