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@ARTICLE{HassaniNia:490287,
      author       = {Hassani Nia, Fatemeh and Woike, Daniel and Bento, Isabel
                      and Niebling, Stephan and Tibbe, Debora and Schulz, Kristina
                      and Hirnet, Daniela and Skiba, Matilda and Hönck,
                      Hans-Hinrich and Veith, Katharina and Günther, Christian
                      and Scholz, Tasja and Bierhals, Tatjana and Driemeyer,
                      Joenna and Bend, Renee and Failla, Antonio Virgilio and
                      Lohr, Christian and Alai, Maria Garcia and Kreienkamp,
                      Hans-Jürgen},
      title        = {{S}tructural deficits in key domains of {S}hank2 lead to
                      alterations in postsynaptic nanoclusters and to a
                      neurodevelopmental disorder in humans},
      journal      = {Molecular psychiatry},
      volume       = {29},
      number       = {6},
      issn         = {1359-4184},
      address      = {London},
      publisher    = {Macmillan},
      reportid     = {PUBDB-2022-07620},
      pages        = {1683 - 1697},
      year         = {2022},
      abstract     = {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 Zn2+-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 Zn2+-dependent
                      polymerization of the Shank2-SAM domain. Structural analysis
                      shows that Trp1800 dislodges one histidine crucial for Zn2+
                      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 Zn2+. 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.},
      cin          = {EMBL-User / EMBL / CSSB-EMBL / CSSB-CF-SPC},
      ddc          = {610},
      cid          = {I:(DE-H253)EMBL-User-20120814 / I:(DE-H253)EMBL-20120731 /
                      I:(DE-H253)CSSB-EMBL-20141216 /
                      I:(DE-H253)CSSB-CF-SPC-20210520},
      pnm          = {6G3 - PETRA III (DESY) (POF4-6G3)},
      pid          = {G:(DE-HGF)POF4-6G3},
      experiment   = {EXP:(DE-H253)P-P14-20150101},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:36450866},
      UT           = {WOS:000912572000001},
      doi          = {10.1038/s41380-022-01882-3},
      url          = {https://bib-pubdb1.desy.de/record/490287},
}