6KYH

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

Summary for 6KYH

• Entry DOI: 10.2210/pdb6kyh/pdb
• Descriptor: SH3 and multiple ankyrin repeat domains protein 3, GTPase HRas, PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER, ... (4 entities in total)
• Functional Keywords: shank3, gtpase, synaptic scaffold protein, structural protein-signaling protein complex, structural protein/signaling protein
• Biological source: Mus musculus (Mouse); More
• Total number of polymer chains: 8
• Total formula weight: 240414.66

Authors

Cai, Q.,Zhang, M. (deposition date: 2019-09-18, release date: 2019-12-04, Last modification date: 2023-11-22)

Primary citation

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, 28:290-, 2020

PubMed Abstract: 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.

PubMed: 31879129
DOI: 10.1016/j.str.2019.11.018

Experimental method

X-RAY DIFFRACTION (3.3 Å)