XB-ART-52846
J Biol Chem
2016 Jun 24;29126:13875-90. doi: 10.1074/jbc.M116.724294.
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Investigation of the Interaction between Cdc42 and Its Effector TOCA1: HANDOVER OF Cdc42 TO THE ACTIN REGULATOR N-WASP IS FACILITATED BY DIFFERENTIAL BINDING AFFINITIES.
Watson JR
,
Fox HM
,
Nietlispach D
,
Gallop JL
,
Owen D
,
Mott HR
.
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Transducer of Cdc42-dependent actin assembly protein 1 (TOCA1) is an effector of the Rho family small G protein Cdc42. It contains a membrane-deforming F-BAR domain as well as a Src homology 3 (SH3) domain and a G protein-binding homology region 1 (HR1) domain. TOCA1 binding to Cdc42 leads to actin rearrangements, which are thought to be involved in processes such as endocytosis, filopodia formation, and cell migration. We have solved the structure of the HR1 domain of TOCA1, providing the first structural data for this protein. We have found that the TOCA1 HR1, like the closely related CIP4 HR1, has interesting structural features that are not observed in other HR1 domains. We have also investigated the binding of the TOCA HR1 domain to Cdc42 and the potential ternary complex between Cdc42 and the G protein-binding regions of TOCA1 and a member of the Wiskott-Aldrich syndrome protein family, N-WASP. TOCA1 binds Cdc42 with micromolar affinity, in contrast to the nanomolar affinity of the N-WASP G protein-binding region for Cdc42. NMR experiments show that the Cdc42-binding domain from N-WASP is able to displace TOCA1 HR1 from Cdc42, whereas the N-WASP domain but not the TOCA1 HR1 domain inhibits actin polymerization. This suggests that TOCA1 binding to Cdc42 is an early step in the Cdc42-dependent pathways that govern actin dynamics, and the differential binding affinities of the effectors facilitate a handover from TOCA1 to N-WASP, which can then drive recruitment of the actin-modifying machinery.
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092096 Wellcome Trust , 281971 European Research Council
Species referenced: Xenopus laevis
Genes referenced: cdc42 fnbp1l pak1 rac1 rho rhoa was
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References [+] :
Abdul-Manan,
Structure of Cdc42 in complex with the GTPase-binding domain of the 'Wiskott-Aldrich syndrome' protein.
1999, Pubmed
Abdul-Manan, Structure of Cdc42 in complex with the GTPase-binding domain of the 'Wiskott-Aldrich syndrome' protein. 1999, Pubmed
Acuner Ozbabacan, Transient protein-protein interactions. 2011, Pubmed
Aspenström, A Cdc42 target protein with homology to the non-kinase domain of FER has a potential role in regulating the actin cytoskeleton. 1997, Pubmed
Bai, A TOCA/CDC-42/PAR/WAVE functional module required for retrograde endocytic recycling. 2015, Pubmed
Bailey, The structure of binder of Arl2 (BART) reveals a novel G protein binding domain: implications for function. 2009, Pubmed
Bourne, The GTPase superfamily: conserved structure and molecular mechanism. 1991, Pubmed
Bu, Cdc42 interaction with N-WASP and Toca-1 regulates membrane tubulation, vesicle formation and vesicle motility: implications for endocytosis. 2010, Pubmed
Bu, The Toca-1-N-WASP complex links filopodial formation to endocytosis. 2009, Pubmed
Buck, A two-state allosteric model for autoinhibition rationalizes WASP signal integration and targeting. 2004, Pubmed
Burbelo, A conserved binding motif defines numerous candidate target proteins for both Cdc42 and Rac GTPases. 1995, Pubmed
Chander, Transducer of Cdc42-dependent actin assembly promotes breast cancer invasion and metastasis. 2013, Pubmed
Cherfils, Regulation of small GTPases by GEFs, GAPs, and GDIs. 2013, Pubmed
de Vries, The HADDOCK web server for data-driven biomolecular docking. 2010, Pubmed
Elliot-Smith, Double mutant cycle thermodynamic analysis of the hydrophobic Cdc42-ACK protein-protein interaction. 2007, Pubmed
Elliot-Smith, Specificity determinants on Cdc42 for binding its effector protein ACK. 2005, Pubmed
Fenwick, The RalB-RLIP76 complex reveals a novel mode of ral-effector interaction. 2010, Pubmed
Fricke, Drosophila Cip4/Toca-1 integrates membrane trafficking and actin dynamics through WASP and SCAR/WAVE. 2009, Pubmed
Gallop, Phosphoinositides and membrane curvature switch the mode of actin polymerization via selective recruitment of toca-1 and Snx9. 2013, Pubmed , Xenbase
Giuliani, Requirements for F-BAR proteins TOCA-1 and TOCA-2 in actin dynamics and membrane trafficking during Caenorhabditis elegans oocyte growth and embryonic epidermal morphogenesis. 2009, Pubmed
Hall, Rho GTPases and the actin cytoskeleton. 1998, Pubmed
Heinig, STRIDE: a web server for secondary structure assignment from known atomic coordinates of proteins. 2004, Pubmed
Hemsath, An electrostatic steering mechanism of Cdc42 recognition by Wiskott-Aldrich syndrome proteins. 2005, Pubmed
Henne, Structure and analysis of FCHo2 F-BAR domain: a dimerizing and membrane recruitment module that effects membrane curvature. 2007, Pubmed
Ho, Toca-1 mediates Cdc42-dependent actin nucleation by activating the N-WASP-WIP complex. 2004, Pubmed , Xenbase
Höning, Phosphatidylinositol-(4,5)-bisphosphate regulates sorting signal recognition by the clathrin-associated adaptor complex AP2. 2005, Pubmed
Hu, Transducer of Cdc42-dependent actin assembly promotes epidermal growth factor-induced cell motility and invasiveness. 2011, Pubmed
Hutchinson, Mutational analysis reveals a single binding interface between RhoA and its effector, PRK1. 2011, Pubmed
Hutchinson, Differential binding of RhoA, RhoB, and RhoC to protein kinase C-related kinase (PRK) isoforms PRK1, PRK2, and PRK3: PRKs have the highest affinity for RhoB. 2013, Pubmed
Itoh, Dynamin and the actin cytoskeleton cooperatively regulate plasma membrane invagination by BAR and F-BAR proteins. 2005, Pubmed
Kakimoto, Regulation of neuronal morphology by Toca-1, an F-BAR/EFC protein that induces plasma membrane invagination. 2006, Pubmed
Kim, Autoinhibition and activation mechanisms of the Wiskott-Aldrich syndrome protein. 2000, Pubmed
Kobashigawa, The NMR structure of the TC10- and Cdc42-interacting domain of CIP4. 2009, Pubmed
Kozma, The Ras-related protein Cdc42Hs and bradykinin promote formation of peripheral actin microspikes and filopodia in Swiss 3T3 fibroblasts. 1995, Pubmed
Kühn, Formins as effector proteins of Rho GTPases. 2014, Pubmed
Lebensohn, Activation of the WAVE complex by coincident signals controls actin assembly. 2009, Pubmed
Lee, Self-assembly of filopodia-like structures on supported lipid bilayers. 2010, Pubmed , Xenbase
Leung, The nucleotide switch in Cdc42 modulates coupling between the GTPase-binding and allosteric equilibria of Wiskott-Aldrich syndrome protein. 2005, Pubmed
Ma, The Arp2/3 complex mediates actin polymerization induced by the small GTP-binding protein Cdc42. 1998, Pubmed , Xenbase
Ma, Corequirement of specific phosphoinositides and small GTP-binding protein Cdc42 in inducing actin assembly in Xenopus egg extracts. 1998, Pubmed , Xenbase
Machesky, Signaling to actin dynamics. 1999, Pubmed
Machesky, Rho: a connection between membrane receptor signalling and the cytoskeleton. 1996, Pubmed
Maesaki, The structural basis of Rho effector recognition revealed by the crystal structure of human RhoA complexed with the effector domain of PKN/PRK1. 1999, Pubmed
Miki, WAVE, a novel WASP-family protein involved in actin reorganization induced by Rac. 1998, Pubmed
Miki, Direct binding of the verprolin-homology domain in N-WASP to actin is essential for cytoskeletal reorganization. 1998, Pubmed
Miyamoto, Nuclear actin polymerization is required for transcriptional reprogramming of Oct4 by oocytes. 2011, Pubmed , Xenbase
Modha, The Rac1 polybasic region is required for interaction with its effector PRK1. 2008, Pubmed
Mott, Structures of Ras superfamily effector complexes: What have we learnt in two decades? 2015, Pubmed
Mott, Structure of the small G protein Cdc42 bound to the GTPase-binding domain of ACK. 1999, Pubmed
Nakamura, Structural basis for membrane binding specificity of the Bin/Amphiphysin/Rvs (BAR) domain of Arfaptin-2 determined by Arl1 GTPase. 2012, Pubmed
Nobes, Rho, rac, and cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia. 1995, Pubmed
Owen, Molecular dissection of the interaction between the small G proteins Rac1 and RhoA and protein kinase C-related kinase 1 (PRK1). 2003, Pubmed
Owen, The IQGAP1-Rac1 and IQGAP1-Cdc42 interactions: interfaces differ between the complexes. 2008, Pubmed
Owen, Residues in Cdc42 that specify binding to individual CRIB effector proteins. 2000, Pubmed
Padrick, Physical mechanisms of signal integration by WASP family proteins. 2010, Pubmed
Perkins, Transient protein-protein interactions: structural, functional, and network properties. 2010, Pubmed
Praefcke, Evolving nature of the AP2 alpha-appendage hub during clathrin-coated vesicle endocytosis. 2004, Pubmed
Ridley, The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors. 1992, Pubmed
Ridley, Rho: theme and variations. 1996, Pubmed
Ridley, The small GTP-binding protein rac regulates growth factor-induced membrane ruffling. 1992, Pubmed
Rieping, ARIA2: automated NOE assignment and data integration in NMR structure calculation. 2007, Pubmed
Rohatgi, The interaction between N-WASP and the Arp2/3 complex links Cdc42-dependent signals to actin assembly. 1999, Pubmed , Xenbase
Rohatgi, Mechanism of N-WASP activation by CDC42 and phosphatidylinositol 4, 5-bisphosphate. 2000, Pubmed , Xenbase
Rudolph, The Cdc42/Rac interactive binding region motif of the Wiskott Aldrich syndrome protein (WASP) is necessary but not sufficient for tight binding to Cdc42 and structure formation. 1998, Pubmed
Schanda, SOFAST-HMQC experiments for recording two-dimensional heteronuclear correlation spectra of proteins within a few seconds. 2005, Pubmed
Schmid, Integrating molecular and network biology to decode endocytosis. 2007, Pubmed
Shen, Protein backbone and sidechain torsion angles predicted from NMR chemical shifts using artificial neural networks. 2013, Pubmed
Symons, Wiskott-Aldrich syndrome protein, a novel effector for the GTPase CDC42Hs, is implicated in actin polymerization. 1996, Pubmed
Takano, EFC/F-BAR proteins and the N-WASP-WIP complex induce membrane curvature-dependent actin polymerization. 2008, Pubmed
ten Klooster, Targeting and activation of Rac1 are mediated by the exchange factor beta-Pix. 2006, Pubmed
Thompson, Delineation of the Cdc42/Rac-binding domain of p21-activated kinase. 1998, Pubmed
Tsujita, Coordination between the actin cytoskeleton and membrane deformation by a novel membrane tubulation domain of PCH proteins is involved in endocytosis. 2006, Pubmed
Van Itallie, A complex of ZO-1 and the BAR-domain protein TOCA-1 regulates actin assembly at the tight junction. 2015, Pubmed
Vetter, The guanine nucleotide-binding switch in three dimensions. 2001, Pubmed
Vranken, The CCPN data model for NMR spectroscopy: development of a software pipeline. 2005, Pubmed
Walrant, Triggering actin polymerization in Xenopus egg extracts from phosphoinositide-containing lipid bilayers. 2015, Pubmed , Xenbase
Wang, Single-molecule dynamics reveals cooperative binding-folding in protein recognition. 2006, Pubmed
Watanabe, Protein kinase N (PKN) and PKN-related protein rhophilin as targets of small GTPase Rho. 1996, Pubmed
Watson, (1)H, (13)C and (15)N resonance assignments of the Cdc42-binding domain of TOCA1. 2016, Pubmed , Xenbase
Wu, Calcium oscillations-coupled conversion of actin travelling waves to standing oscillations. 2013, Pubmed