6kyh

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Crystal structure of Shank3 NTD-ANK A42K mutant in complex with HRas

Structural highlights

6kyh is a 8 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 3.3Å
Ligands:GNP, MG
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

Shank1/2/3, major scaffold proteins in excitatory synapses, are frequently mutated in patients with psychiatric disorders. Although the Shank N-terminal domain and ankyrin repeats domain tandem (NTD-ANK) is known to bind to Ras and Rap1, the molecular mechanism underlying and functional significance of the bindings in synapses are unknown. Here, we demonstrate that Shank3 NTD-ANK specifically binds to the guanosine triphosphate (GTP)-bound form of HRas and Rap1. In addition to the canonical site mediated by the Ras-association domain and common to both GTPases, Shank3 contains an unconventional Rap1 binding site formed by NTD and ANK together. Binding of Shank3 to the GTP-loaded Rap1 slows down its GTP hydrolysis by SynGAP. We further show that the interactions between Shank3 and HRas/Rap1 at excitatory synapses are promoted by synaptic activation. Thus, Shank3 may be able to modulate signaling of the Ras family proteins via directly binding to and stabilizing the GTP-bound form of the enzymes.

Shank3 Binds to and Stabilizes the Active Form of Rap1 and HRas GTPases via Its NTD-ANK Tandem with Distinct Mechanisms.,Cai Q, Hosokawa T, Zeng M, Hayashi Y, Zhang M Structure. 2019 Dec 17. pii: S0969-2126(19)30436-8. doi:, 10.1016/j.str.2019.11.018. PMID:31879129[5]

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

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Citations
3 reviews cite this structure
Folding and Stability of Ankyrin Repeats Control Biological Protein Function.
Kumar et al. (2021)
2 more
6 other articles
No citations found

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. ↑ Cai Q, Hosokawa T, Zeng M, Hayashi Y, Zhang M. Shank3 Binds to and Stabilizes the Active Form of Rap1 and HRas GTPases via Its NTD-ANK Tandem with Distinct Mechanisms. Structure. 2019 Dec 17. pii: S0969-2126(19)30436-8. doi:, 10.1016/j.str.2019.11.018. PMID:31879129 doi:http://dx.doi.org/10.1016/j.str.2019.11.018

Contents


PDB ID 6kyh

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