5G4X

The crystal structure of the SHANK3 N-terminus

Summary for 5G4X

• Entry DOI: 10.2210/pdb5g4x/pdb
• Descriptor: SH3 AND MULTIPLE ANKYRIN REPEAT DOMAINS PROTEIN 3, 1,2-ETHANEDIOL (3 entities in total)
• Functional Keywords: structural protein, shank3, ras, integrin.
• Biological source: RATTUS NORVEGICUS (NORWAY RAT)
• Cellular location: Cytoplasm: Q9JLU4
• Total number of polymer chains: 1
• Total formula weight: 40493.68

Authors

Zacharchenko, T.,Barsukov, I. (deposition date: 2016-05-17, release date: 2017-01-25, Last modification date: 2024-01-10)

Primary citation

Lilja, J.,Zacharchenko, T.,Georgiadou, M.,Jacquemet, G.,Franceschi, N.,Peuhu, E.,Hamidi, H.,Pouwels, J.,Martens, V.,Nia, F.H.,Beifuss, M.,Boeckers, T.,Kreienkamp, H.J.,Barsukov, I.L.,Ivaska, J.
SHANK proteins limit integrin activation by directly interacting with Rap1 and R-Ras.
Nat. Cell Biol., 19:292-305, 2017

PubMed Abstract: SHANK3, a synaptic scaffold protein and actin regulator, is widely expressed outside of the central nervous system with predominantly unknown function. Solving the structure of the SHANK3 N-terminal region revealed that the SPN domain is an unexpected Ras-association domain with high affinity for GTP-bound Ras and Rap G-proteins. The role of Rap1 in integrin activation is well established but the mechanisms to antagonize it remain largely unknown. Here, we show that SHANK1 and SHANK3 act as integrin activation inhibitors by sequestering active Rap1 and R-Ras via the SPN domain and thus limiting their bioavailability at the plasma membrane. Consistently, SHANK3 silencing triggers increased plasma membrane Rap1 activity, cell spreading, migration and invasion. Autism-related mutations within the SHANK3 SPN domain (R12C and L68P) disrupt G-protein interaction and fail to counteract integrin activation along the Rap1-RIAM-talin axis in cancer cells and neurons. Altogether, we establish SHANKs as critical regulators of G-protein signalling and integrin-dependent processes.

PubMed: 28263956
DOI: 10.1038/ncb3487

Experimental method

X-RAY DIFFRACTION (2.166 Å)