7cqf

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

Structural highlights

7cqf is a 1 chain structure with sequence from Homo sapiens and Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.8Å
Ligands:CHT, CL, EDO
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

DLG4_RAT Interacts with the cytoplasmic tail of NMDA receptor subunits and shaker-type potassium channels. Required for synaptic plasticity associated with NMDA receptor signaling. Overexpression or depletion of DLG4 changes the ratio of excitatory to inhibitory synapses in hippocampal neurons. May reduce the amplitude of ASIC3 acid-evoked currents by retaining the channel intracellularly. May regulate the intracellular trafficking of ADR1B.[1] [2] ADA22_HUMAN Probable ligand for integrin in the brain. This is a non catalytic metalloprotease-like protein. Involved in regulation of cell adhesion and spreading and in inhibition of cell proliferation. Neuronal receptor for LGI1.[3] [4] [5]

Publication Abstract from PubMed

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, Kv1 channels, and LRRTM4-Neurexin adhesion molecules. Adam22 (DeltaC5/DeltaC5) 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.

LGI1-ADAM22-MAGUK configures transsynaptic nanoalignment for synaptic transmission and epilepsy prevention.,Fukata Y, Chen X, Chiken S, Hirano Y, Yamagata A, Inahashi H, Sanbo M, Sano H, Goto T, Hirabayashi M, Kornau HC, Pruss H, Nambu A, Fukai S, Nicoll RA, Fukata M Proc Natl Acad Sci U S A. 2021 Jan 19;118(3). pii: 2022580118. doi:, 10.1073/pnas.2022580118. PMID:33397806[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
7 reviews cite this structure
Autoantibodies in neurological disease.
Prüss et al. (2021)
6 more
16 other articles
No citations found

See Also

References

  1. ↑ Hruska-Hageman AM, Benson CJ, Leonard AS, Price MP, Welsh MJ. PSD-95 and Lin-7b interact with acid-sensing ion channel-3 and have opposite effects on H+- gated current. J Biol Chem. 2004 Nov 5;279(45):46962-8. Epub 2004 Aug 17. PMID:15317815 doi:10.1074/jbc.M405874200
  2. ↑ Prange O, Wong TP, Gerrow K, Wang YT, El-Husseini A. A balance between excitatory and inhibitory synapses is controlled by PSD-95 and neuroligin. Proc Natl Acad Sci U S A. 2004 Sep 21;101(38):13915-20. Epub 2004 Sep 9. PMID:15358863 doi:10.1073/pnas.0405939101
  3. ↑ Zhu P, Sun Y, Xu R, Sang Y, Zhao J, Liu G, Cai L, Li C, Zhao S. The interaction between ADAM 22 and 14-3-3zeta: regulation of cell adhesion and spreading. Biochem Biophys Res Commun. 2003 Feb 21;301(4):991-9. PMID:12589811
  4. ↑ Zhu P, Sang Y, Xu H, Zhao J, Xu R, Sun Y, Xu T, Wang X, Chen L, Feng H, Li C, Zhao S. ADAM22 plays an important role in cell adhesion and spreading with the assistance of 14-3-3. Biochem Biophys Res Commun. 2005 Jun 17;331(4):938-46. PMID:15882968 doi:http://dx.doi.org/10.1016/j.bbrc.2005.03.229
  5. ↑ D'Abaco GM, Ng K, Paradiso L, Godde NJ, Kaye A, Novak U. ADAM22, expressed in normal brain but not in high-grade gliomas, inhibits cellular proliferation via the disintegrin domain. Neurosurgery. 2006 Jan;58(1):179-86; discussion 179-86. PMID:16385342
  6. ↑ Fukata Y, Chen X, Chiken S, Hirano Y, Yamagata A, Inahashi H, Sanbo M, Sano H, Goto T, Hirabayashi M, Kornau HC, Pruss H, Nambu A, Fukai S, Nicoll RA, Fukata M. LGI1-ADAM22-MAGUK configures transsynaptic nanoalignment for synaptic transmission and epilepsy prevention. Proc Natl Acad Sci U S A. 2021 Jan 19;118(3). pii: 2022580118. doi:, 10.1073/pnas.2022580118. PMID:33397806 doi:http://dx.doi.org/10.1073/pnas.2022580118

Contents


PDB ID 7cqf

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