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Instruments / Technical Area	Publication Details	Published	Actions
I24-Microfocus Macromolecular Crystallography	RPEL-family rhoGAPs link Rac/Cdc42 GTP loading to G-actin availability Jessica Diring , Stephane Mouilleron , Neil Q. Mcdonald , Richard Treisman Nature Cell Biology DOI: 10.1038/s41556-019-0337-y Diamond Proposal Number(s): [8015] Show Abstract ▼ Abstract: RPEL proteins, which contain the G-actin-binding RPEL motif, coordinate cytoskeletal processes with actin dynamics. We show that the ArhGAP12- and ArhGAP32-family GTPase-activating proteins (GAPs) are RPEL proteins. We determine the structure of the ArhGAP12/G-actin complex, and show that G-actin contacts the RPEL motif and GAP domain sequences. G-actin inhibits ArhGAP12 GAP activity, and this requires the G-actin contacts identified in the structure. In B16 melanoma cells, ArhGAP12 suppresses basal Rac and Cdc42 activity, F-actin assembly, invadopodia formation and experimental metastasis. In this setting, ArhGAP12 mutants defective for G-actin binding exhibit more effective downregulation of Rac GTP loading following HGF stimulation and enhanced inhibition of Rac-dependent processes, including invadopodia formation. Potentiation or disruption of the G-actin/ArhGAP12 interaction, by treatment with the actin-binding drugs latrunculin B or cytochalasin D, has corresponding effects on Rac GTP loading. The interaction of G-actin with RPEL-family rhoGAPs thus provides a negative feedback loop that couples Rac activity to actin dynamics.	Jun 2019
I04-1-Macromolecular Crystallography (fixed wavelength)	SHANK proteins limit integrin activation by directly interacting with Rap1 and R-Ras Johanna Lilja , Thomas Zacharchenko , Maria Georgiadou , Guillaume Jacquemet , Nicola de Franceschi , Emilia Peuhu , Hellyeh Hamidi , Jeroen Pouwels , Victoria Martens , Fatemeh hassani Nia , Malte Beifuss , Tobias Boeckers , Hans-Juergen Kreienkamp , Igor l. Barsukov , Johanna Ivaska Nature Cell Biology 19, 292 - 305 DOI: 10.1038/ncb3487 Show Abstract ▼ 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.	Mar 2017

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