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Gene Review

Shank1  -  SH3 and multiple ankyrin repeat domains 1

Rattus norvegicus

Synonyms: GKAP/SAPAP-interacting protein, SH3 and multiple ankyrin repeat domains protein 1, SPANK-1, SSTR-interacting protein, SSTRIP, ...
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Disease relevance of Shank1

  • These data revealed a close association between the expression and loss of allodynia and hyperalgesia with changes in the levels of Homer1b/c and Shank1a in the spinal dorsal horn [1].

High impact information on Shank1

  • These mobile clusters contain the scaffolding proteins PSD-95, GKAP, and Shank [2].
  • Targeted to the PSD by a PDZ-dependent mechanism, Shank promotes the maturation of dendritic spines and the enlargement of spine heads via its ability to recruit Homer to postsynaptic sites [3].
  • These data suggest a central role for the Shank scaffold in the structural and functional organization of the dendritic spine and synaptic junction [3].
  • The Shank family of proteins interacts with NMDA receptor and metabotropic glutamate receptor complexes in the postsynaptic density (PSD) [3].
  • Homer EVH1 (Ena/VASP Homology 1) domains interact with proline-rich motifs in the cytoplasmic regions of group 1 metabotropic glutamate receptors (mGluRs), inositol-1,4,5-trisphosphate receptors (IP3Rs), and Shank proteins [4].

Biological context of Shank1

  • Shank contains multiple protein-protein interaction sites, including ankyrin repeats, an SH3 domain, a PDZ domain, a long proline-rich region and an SAM domain [5].
  • In yeast two-hybrid screen of rat brain cDNA library with the C-terminal bait of CaV1.3a (long C-terminal splice variant) L-type Ca2+ channel subunit, we isolated multiple clones of postsynaptic adaptor protein Shank [6].
  • Overexpression of the C-terminal region of Shank containing the Homer binding site causes effects similar to those of Homer1a [7].
  • Key role of the postsynaptic density scaffold proteins Shank and Homer in the functional architecture of Ca2+ homeostasis at dendritic spines in hippocampal neurons [8].
  • Bioavailability to rats of calcium in meat products prepared from hand or mechanically deboned beef shank [9].

Anatomical context of Shank1


Associations of Shank1 with chemical compounds

  • The PDZ domain of Shank1 from Rattus norvegicus and its complex with the C-terminal octapeptide of GKAP were crystallized at 294 K using polyethylene glycol 20 000 and 6000 as precipitants [5].
  • ProSAP/Shank postsynaptic density proteins interact with insulin receptor tyrosine kinase substrate IRSp53 [12].
  • The ProSAP/Shank family of multidomain proteins of the postsynaptic density (PSD) can either directly or indirectly interact with NMDA-type and metabotropic glutamate receptors and the actin-based cytoskeleton [12].
  • In experiments with dominant-negative peptides and dihydropyridine-resistant CaV1.3a mutants, we demonstrated an importance of Shank-binding motif in CaV1.3a sequence for phosphorylated cAMP response element-binding protein (pCREB) signaling in cultured hippocampal neurons [6].
  • Furthermore, two additional components of the well characterized glutamatergic postsynaptic complex, GKAP/SAPAP (guanylate kinase domain-associated protein/synapse-associated protein-associated protein) and Shank/ProSAP family proteins, are also present at neuronal cholinergic synapses [13].

Regulatory relationships of Shank1

  • The overexpression of the mutant of the EVH1 domain or deletion of the extreme C-terminal leucine zipper motif markedly suppressed the synaptic localization of endogenous shank but not PSD-95 or GKAP [14].

Other interactions of Shank1

  • We studied the synaptic targeting of multi-domain proteins of the ProSAP/Shank family thought to serve as master scaffolding molecules of the postsynaptic density [15].
  • SAPAP also binds the recently identified proteins, nArgBP2 and synamon (also called Shank 1a), via the proline-rich region and the C-terminus, respectively [16].
  • In this study we examined whether the expression and loss of behavioral signs of neuropathic pain were associated with changes in the content of the scaffolding proteins Homer and Shank in the post-synaptic density (PSD) of the spinal dorsal horn [1].
  • SAPAP1 also interacts with various proteins, including neurofilaments, synaptic scaffolding molecule (S-SCAM), nArgBP2, dynein light chain and Shank through different regions [17].
  • PSD-Zip45/Homer1c, which contains an enabled/VASP homology 1 (EVH1) domain and leucine zipper motifs, is a postsynaptic density (PSD) scaffold protein that interacts with metabotropic glutamate receptors and the shank family [14].

Analytical, diagnostic and therapeutic context of Shank1

  • Crystallization and preliminary X-ray crystallographic studies of the PDZ domain of Shank1 from Rattus norvegicus [5].
  • In contrast, there were no differences in the PSD content of Homer1b/c and Shank1a in the dorsal horn of control or sham-operated animals and ligated animals in which the thermal hyperalgesia and differential weight-bearing behavior had disappeared 28 days after the loose ligation [1].
  • Swelling was induced (i) by the application of pressure (15 cmH2O) to the shank of the patch pipette, (ii) by exposing the cells to hypotonic solutions and (iii) as a consequence of leakage of electrolyte from an intracellular microelectrode [18].


  1. Increased levels of Homer1b/c and Shank1a in the post-synaptic density of spinal dorsal horn neurons are associated with neuropathic pain in rats. Miletic, G., Miyabe, T., Gebhardt, K.J., Miletic, V. Neurosci. Lett. (2005) [Pubmed]
  2. A preformed complex of postsynaptic proteins is involved in excitatory synapse development. Gerrow, K., Romorini, S., Nabi, S.M., Colicos, M.A., Sala, C., El-Husseini, A. Neuron (2006) [Pubmed]
  3. Regulation of dendritic spine morphology and synaptic function by Shank and Homer. Sala, C., Piëch, V., Wilson, N.R., Passafaro, M., Liu, G., Sheng, M. Neuron (2001) [Pubmed]
  4. Structure of the Homer EVH1 domain-peptide complex reveals a new twist in polyproline recognition. Beneken, J., Tu, J.C., Xiao, B., Nuriya, M., Yuan, J.P., Worley, P.F., Leahy, D.J. Neuron (2000) [Pubmed]
  5. Crystallization and preliminary X-ray crystallographic studies of the PDZ domain of Shank1 from Rattus norvegicus. Park, S.H., Im, Y.J., Rho, S.H., Lee, J.H., Yang, S., Kim, E., Eom, S.H. Acta Crystallogr. D Biol. Crystallogr. (2002) [Pubmed]
  6. Association of CaV1.3 L-type calcium channels with Shank. Zhang, H., Maximov, A., Fu, Y., Xu, F., Tang, T.S., Tkatch, T., Surmeier, D.J., Bezprozvanny, I. J. Neurosci. (2005) [Pubmed]
  7. Inhibition of dendritic spine morphogenesis and synaptic transmission by activity-inducible protein Homer1a. Sala, C., Futai, K., Yamamoto, K., Worley, P.F., Hayashi, Y., Sheng, M. J. Neurosci. (2003) [Pubmed]
  8. Key role of the postsynaptic density scaffold proteins Shank and Homer in the functional architecture of Ca2+ homeostasis at dendritic spines in hippocampal neurons. Sala, C., Roussignol, G., Meldolesi, J., Fagni, L. J. Neurosci. (2005) [Pubmed]
  9. Bioavailability to rats of calcium in meat products prepared from hand or mechanically deboned beef shank. Tso, T.B., McLaughlin, K., Mahoney, A.W., Hendricks, D.G. J. Nutr. (1984) [Pubmed]
  10. Differential expression and dendritic transcript localization of Shank family members: identification of a dendritic targeting element in the 3' untranslated region of Shank1 mRNA. Böckers, T.M., Segger-Junius, M., Iglauer, P., Bockmann, J., Gundelfinger, E.D., Kreutz, M.R., Richter, D., Kindler, S., Kreienkamp, H.J. Mol. Cell. Neurosci. (2004) [Pubmed]
  11. Synamon, a novel neuronal protein interacting with synapse-associated protein 90/postsynaptic density-95-associated protein. Yao, I., Hata, Y., Hirao, K., Deguchi, M., Ide, N., Takeuchi, M., Takai, Y. J. Biol. Chem. (1999) [Pubmed]
  12. ProSAP/Shank postsynaptic density proteins interact with insulin receptor tyrosine kinase substrate IRSp53. Bockmann, J., Kreutz, M.R., Gundelfinger, E.D., Böckers, T.M. J. Neurochem. (2002) [Pubmed]
  13. PSD93 regulates synaptic stability at neuronal cholinergic synapses. Parker, M.J., Zhao, S., Bredt, D.S., Sanes, J.R., Feng, G. J. Neurosci. (2004) [Pubmed]
  14. Synaptic targeting of PSD-Zip45 (Homer 1c) and its involvement in the synaptic accumulation of F-actin. Usui, S., Konno, D., Hori, K., Maruoka, H., Okabe, S., Fujikado, T., Tano, Y., Sobue, K. J. Biol. Chem. (2003) [Pubmed]
  15. C-terminal synaptic targeting elements for postsynaptic density proteins ProSAP1/Shank2 and ProSAP2/Shank3. Boeckers, T.M., Liedtke, T., Spilker, C., Dresbach, T., Bockmann, J., Kreutz, M.R., Gundelfinger, E.D. J. Neurochem. (2005) [Pubmed]
  16. Association of synapse-associated protein 90/ postsynaptic density-95-associated protein (SAPAP) with neurofilaments. Hirao, K., Hata, Y., Deguchi, M., Yao, I., Ogura, M., Rokukawa, C., Kawabe, H., Mizoguchi, A., Takai, Y. Genes Cells (2000) [Pubmed]
  17. Synaptic localization of SAPAP1, a synaptic membrane-associated protein. Yao, I., Iida, J., Nishimura, W., Hata, Y. Genes Cells (2003) [Pubmed]
  18. Properties of a cell volume-sensitive potassium conductance in isolated guinea-pig and rat hepatocytes. Sandford, C.A., Sweiry, J.H., Jenkinson, D.H. J. Physiol. (Lond.) (1992) [Pubmed]
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