View source for 8b10


==Crystal Structure of Shank2-SAM mutant domain - L1800W==
<StructureSection load='8b10' size='340' side='right'caption='[[8b10]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8b10]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8B10 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8B10 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.95&#8491;</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8b10 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8b10 OCA], [https://pdbe.org/8b10 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8b10 RCSB], [https://www.ebi.ac.uk/pdbsum/8b10 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8b10 ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/SHAN2_HUMAN SHAN2_HUMAN] NON RARE IN EUROPE: Autism. Disease susceptibility is associated with variants affecting the gene represented in this entry.
== Function ==
[https://www.uniprot.org/uniprot/SHAN2_HUMAN SHAN2_HUMAN] Seems to be an adapter protein in the postsynaptic density (PSD) of excitatory synapses that interconnects receptors of the postsynaptic membrane including NMDA-type and metabotropic glutamate receptors, and the actin-based cytoskeleton. May play a role in the structural and functional organization of the dendritic spine and synaptic junction.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Postsynaptic scaffold proteins such as Shank, PSD-95, Homer and SAPAP/GKAP family members establish the postsynaptic density of glutamatergic synapses through a dense network of molecular interactions. Mutations in SHANK genes are associated with neurodevelopmental disorders including autism and intellectual disability. However, no SHANK missense mutations have been described which interfere with the key functions of Shank proteins believed to be central for synapse formation, such as GKAP binding via the PDZ domain, or Zn(2+)-dependent multimerization of the SAM domain. We identify two individuals with a neurodevelopmental disorder carrying de novo missense mutations in SHANK2. The p.G643R variant distorts the binding pocket for GKAP in the Shank2 PDZ domain and prevents interaction with Thr(-2) in the canonical PDZ ligand motif of GKAP. The p.L1800W variant severely delays the kinetics of Zn(2+)-dependent polymerization of the Shank2-SAM domain. Structural analysis shows that Trp1800 dislodges one histidine crucial for Zn(2+) binding. The resulting conformational changes block the stacking of helical polymers of SAM domains into sheets through side-by-side contacts, which is a hallmark of Shank proteins, thereby disrupting the highly cooperative assembly process induced by Zn(2+). Both variants reduce the postsynaptic targeting of Shank2 in primary cultured neurons and alter glutamatergic synaptic transmission. Super-resolution microscopy shows that both mutants interfere with the formation of postsynaptic nanoclusters. Our data indicate that both the PDZ- and the SAM-mediated interactions of Shank2 contribute to the compaction of postsynaptic protein complexes into nanoclusters, and that deficiencies in this process interfere with normal brain development in humans.

Structural deficits in key domains of Shank2 lead to alterations in postsynaptic nanoclusters and to a neurodevelopmental disorder in humans.,Hassani Nia F, Woike D, Bento I, Niebling S, Tibbe D, Schulz K, Hirnet D, Skiba M, Honck HH, Veith K, Gunther C, Scholz T, Bierhals T, Driemeyer J, Bend R, Failla AV, Lohr C, Alai MG, Kreienkamp HJ Mol Psychiatry. 2024 Jun;29(6):1683-1697. doi: 10.1038/s41380-022-01882-3. Epub , 2022 Nov 30. PMID:36450866<ref>PMID:36450866</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8b10" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Bento I]]
[[Category: Gracia Alai M]]
[[Category: Kreienkamp J-H]]