5izu

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A new binding site outside the canonical PDZ domain determines the specific interaction between Shank and SAPAP and their function

Structural highlights

5izu is a 4 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.494Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

SHAN3_MOUSE Major scaffold postsynaptic density protein which interacts with multiple proteins and complexes to orchestrate the dendritic spine and synapse formation, maturation and maintenance. Interconnects receptors of the postsynaptic membrane including NMDA-type and metabotropic glutamate receptors via complexes with GKAP/PSD-95 and HOMER, respectively, and the actin-based cytoskeleton. Plays a role in the structural and functional organization of the dendritic spine and synaptic junction through the interaction with Arp2/3 and WAVE1 complex as well as the promotion of the F-actin clusters. By way of this control of actin dynamics, participates in the regulation of developing neurons growth cone motility and the NMDA receptor-signaling. Also modulates GRIA1 exocytosis and GRM5/MGLUR5 expression and signaling to control the AMPA and metabotropic glutamate receptor-mediated synaptic transmission and plasticity. May be required at an early stage of synapse formation and be inhibited by IGF1 to promote synapse maturation.[1] [2] [3] [4]

Publication Abstract from PubMed

Shank and SAPAP (synapse-associated protein 90/postsynaptic density-95-associated protein) are two highly abundant scaffold proteins that directly interact with each other to regulate excitatory synapse development and plasticity. Mutations of SAPAP, but not other reported Shank PDZ domain binders, share a significant overlap on behavioral abnormalities with the mutations of Shank both in patients and in animal models. The molecular mechanism governing the exquisite specificity of the Shank/SAPAP interaction is not clear, however. Here we report that a sequence preceding the canonical PDZ domain of Shank, together with the elongated PDZ BC loop, form another binding site for a sequence upstream of the SAPAP PDZ-binding motif, leading to a several hundred-fold increase in the affinity of the Shank/SAPAP interaction. We provide evidence that the specific interaction afforded by this newly identified site is required for Shank synaptic targeting and the Shank-induced synaptic activity increase. Our study provides a molecular explanation of how Shank and SAPAP dosage changes due to their gene copy number variations can contribute to different psychiatric disorders.

A binding site outside the canonical PDZ domain determines the specific interaction between Shank and SAPAP and their function.,Zeng M, Shang Y, Guo T, He Q, Yung WH, Liu K, Zhang M Proc Natl Acad Sci U S A. 2016 May 16. pii: 201523265. PMID:27185935[5]

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

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Citations
5 reviews cite this structure
International Union of Basic and Clinical Pharmacology. CV. Somatostatin Receptors: Structure, Function, Ligands, and New Nomenclature.
Günther et al. (2018)
4 more
15 other articles
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See Also

References

  1. ↑ Peca J, Feliciano C, Ting JT, Wang W, Wells MF, Venkatraman TN, Lascola CD, Fu Z, Feng G. Shank3 mutant mice display autistic-like behaviours and striatal dysfunction. Nature. 2011 Apr 28;472(7344):437-42. doi: 10.1038/nature09965. Epub 2011 Mar 20. PMID:21423165 doi:http://dx.doi.org/10.1038/nature09965
  2. ↑ Wang X, McCoy PA, Rodriguiz RM, Pan Y, Je HS, Roberts AC, Kim CJ, Berrios J, Colvin JS, Bousquet-Moore D, Lorenzo I, Wu G, Weinberg RJ, Ehlers MD, Philpot BD, Beaudet AL, Wetsel WC, Jiang YH. Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3. Hum Mol Genet. 2011 Aug 1;20(15):3093-108. doi: 10.1093/hmg/ddr212. Epub 2011 May, 10. PMID:21558424 doi:http://dx.doi.org/10.1093/hmg/ddr212
  3. ↑ Raynaud F, Janossy A, Dahl J, Bertaso F, Perroy J, Varrault A, Vidal M, Worley PF, Boeckers TM, Bockaert J, Marin P, Fagni L, Homburger V. Shank3-Rich2 interaction regulates AMPA receptor recycling and synaptic long-term potentiation. J Neurosci. 2013 Jun 5;33(23):9699-715. doi: 10.1523/JNEUROSCI.2725-12.2013. PMID:23739967 doi:http://dx.doi.org/10.1523/JNEUROSCI.2725-12.2013
  4. ↑ Han K, Holder JL Jr, Schaaf CP, Lu H, Chen H, Kang H, Tang J, Wu Z, Hao S, Cheung SW, Yu P, Sun H, Breman AM, Patel A, Lu HC, Zoghbi HY. SHANK3 overexpression causes manic-like behaviour with unique pharmacogenetic properties. Nature. 2013 Nov 7;503(7474):72-7. doi: 10.1038/nature12630. Epub 2013 Oct 23. PMID:24153177 doi:http://dx.doi.org/10.1038/nature12630
  5. ↑ Zeng M, Shang Y, Guo T, He Q, Yung WH, Liu K, Zhang M. A binding site outside the canonical PDZ domain determines the specific interaction between Shank and SAPAP and their function. Proc Natl Acad Sci U S A. 2016 May 16. pii: 201523265. PMID:27185935 doi:http://dx.doi.org/10.1073/pnas.1523265113

Contents


PDB ID 5izu

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