A Stretch of Polybasic Residues Mediates Cdc42 GTPase-activating Protein (CdGAP) Binding to Phosphatidylinositol 3,4,5-Trisphosphate and Regulates Its GAP Activity

Karimzadeh, F.; Primeau, Martin; Mountassif, Driss; Rouiller, Isabelle; Lamarche-Vane, Nathalie

doi:10.1074/jbc.m112.344606

Cited by 14 publications

(16 citation statements)

References 41 publications

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“…The cysteine-flanked KNKEKK segment of serum protein β 2 -glycoprotein 1 crucially binds to cardiolipin, enabling its role in anti-cardiolipin-mediated thrombosis, which is completely abolished by triple mutation KNGEGG [ 76 , 77 ]. Likewise, deletion of the highly-conserved polybasic consensus Kx(R/K)xxKQKxK(R/K/Q)(R/K) from the membrane-targeting human Cd42 GTPase-activating protein results in impaired PI(3,4,5)P 3 interaction and consequently, abolishes Cd42 activity in vivo [ 78 ]. Furthermore, although most PIP recognition and binding domains share little sequence similarities, the small cysteine-rich Zn 2+ -binding ‘Fab1, YOTB, Vac1, EEA1’ (FYVE) domains exhibit the most obvious (R/K)(R/K)HHCR pattern within their binding pocket for PI(3)P [ 79 ].…”

Section: Discussionmentioning

confidence: 99%

Human β-defensin 3 contains an oncolytic motif that binds PI(4,5)P2 to mediate tumour cell permeabilisation

et al. 2015

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Cationic antimicrobial peptides (CAPs), including taxonomically diverse defensins, are innate defense molecules that display potent antimicrobial and immunomodulatory activities. Specific CAPs have also been shown to possess anticancer activities; however, their mechanisms of action are not well defined. Recently, the plant defensin NaD1 was shown to induce tumour cell lysis by directly binding to the plasma membrane phosphoinositide, phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2). The NaD1–lipid interaction was structurally defined by X-ray crystallography, with the defensin forming a dimer that binds PI(4,5)P2 via its cationic β2-β3 loops in a ‘cationic grip’ conformation. In this study, we show that human β-defensin 3 (HBD-3) contains a homologous β2-β3 loop that binds phosphoinositides. The binding of HBD-3 to PI(4,5)P2 was shown to be critical for mediating cytolysis of tumour cells, suggesting a conserved mechanism of action for defensins across diverse species. These data not only identify an evolutionary conservation of CAP structure and function for lipid binding, but also suggest that PIP-binding CAPs could be exploited for novel multifunction therapeutics.

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Section: Discussionmentioning

confidence: 99%

Human β-defensin 3 contains an oncolytic motif that binds PI(4,5)P2 to mediate tumour cell permeabilisation

et al. 2015

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“…cdGAPs contain a polybasic region (PBR) able to interact with PtdIns(3,4,5)P 3 and this binding is required for full inactivation of Rac1 signaling. 87,88 PtdIns(3,4,5)P 3 -binding domains have been also identified in other GAPs, such as p190 Rho-GAPs that possess a PBR (polybasic region) domain able to recognize phosphorylated lipids, 89,90 and the ArhGAP family, characterized by a PH domain. 91 In particular, ArhGAP15 has been suggested to be activated downstream of PI3Kg and to negatively regulate Rac activity in C5a-stimulated bone marrow-derived macrophages.…”

Section: Class I Pi3kmentioning

confidence: 99%

Crossroads of PI3K and Rac pathways

et al. 2015

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Rac and PI3Ks are intracellular signal transducers able to regulate multiple signaling pathways fundamental for cell behavior. PI3Ks are lipid kinases that produce phosphorylated lipids which, in turn, transduce extracellular cues within the cell, while Rac is a small G protein that impacts on actin organization. Compelling evidence indicates that in multiple circumstances the 2 signaling pathways appear intermingled. For instance, phosphorylated lipids produced by PI3Ks recruit and activate GEF and GAP proteins, key modulators of Rac function. Conversely, PI3Ks interact with activated Rac, leading to Rac signaling amplification. This review summarizes the molecular mechanisms underlying the cross-talk between Rac and PI3K signaling in 2 different processes, cell migration and ROS production.

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“…Recent reports indicate that the interaction of different lipids with RhoGAP proteins can trigger GAP activity or modify substrate preferences for a particular GTPase (Ligeti et al, 2004;Ligeti and Settleman, 2006;Lévay et al, 2009;Erlmann et al, 2009;Karimzadeh et al, 2012). For example, the interaction of PA with p190RhoGAP is mediated by a polybasic region and inhibits GAP activity for Rho without affecting GAP activity for Rac (Ligeti and Settleman, 2006).…”

Section: Discussionmentioning

confidence: 99%

A new nucleocytoplasmic RhoGAP protein contributes to control the pathogenicity ofEntamoeba histolyticaby regulating EhRacC and EhRacD activity

Hernandez-Flores¹,

Almaráz-Barrera²,

Lozano-Amado³

et al. 2016

Cellular Microbiology

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Small GTPases are signalling molecules that regulate important cellular processes. GTPases are deactivated by GTPase-activating proteins (GAPs). While human GAPs have been intensively studied, no GAP has yet been characterized in Entamoeba histolytica. In this study, we identified and characterized a novel nucleocytoplasmic RhoGAP in E. histolytica termed EhRhoGAPnc. In silico analyses of the domain structure revealed a previously undescribed peptide region within the carboxy-terminal region of EhRhoGAPnc capable of interacting with phosphatidic acid and phosphatidylinositol 3,5-bisphosphate. The full structural GAP domain showed increase GAP activity compared with the minimum region able to display GAP activity, as analysed both by experimental assays and molecular dynamics simulations. Furthermore, we identified amino acid residues that promote interactions between EhRhoGAPnc and its target GTPases EhRacC and EhRacD. Immunofluorescence studies revealed that EhRhoGAPnc colocalized with EhRacC and EhRacD during uroid formation but not during erythrophagocytosis. Interestingly, during erythrophagocytosis of red blood cells, EhRhoGAPnc colocalized with phosphatidic acid and phosphatidylinositol 3,5-bisphosphate. Overexpression of EhRhoGAPnc in E. histolytica led to inhibition of actin adhesion plate formation, migration, adhesion of E. histolytica to MDCK cells and consequently to an impairment of the cytopathic activity.

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A Stretch of Polybasic Residues Mediates Cdc42 GTPase-activating Protein (CdGAP) Binding to Phosphatidylinositol 3,4,5-Trisphosphate and Regulates Its GAP Activity

Cited by 14 publications

References 41 publications

Human β-defensin 3 contains an oncolytic motif that binds PI(4,5)P2 to mediate tumour cell permeabilisation

Human β-defensin 3 contains an oncolytic motif that binds PI(4,5)P2 to mediate tumour cell permeabilisation

Crossroads of PI3K and Rac pathways

A new nucleocytoplasmic RhoGAP protein contributes to control the pathogenicity ofEntamoeba histolyticaby regulating EhRacC and EhRacD activity

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