title: Structural Basis for the Subversion of MAP Kinase Signaling by an Intrinsically Disordered Parasite Secreted Agonist.
abstract: The causative agent of toxoplasmosis, the intracellular parasite Toxoplasma gondii, delivers a protein, GRA24, into the cells it infects that interacts with the mitogen-activated protein (MAP) kinase p38α (MAPK14), leading to activation and nuclear translocation of the host kinase and a subsequent inflammatory response that controls the progress of the parasite. The purification of a recombinant complex of GRA24 and human p38α has allowed the molecular basis of this activation to be determined. GRA24 is shown to be intrinsically disordered, binding two kinases that act independently, and is the only factor required to bypass the canonical mitogen-activated protein kinase activation pathway. An adapted kinase interaction motif (KIM) forms a highly stable complex that competes with cytoplasmic regulatory partners. In addition, the recombinant complex forms a powerful in vitro tool to evaluate the specificity and effectiveness of p38α inhibitors that have advanced to clinical trials, as it provides a hitherto unavailable stable and highly active form of p38α.
authors.affiliation: European Molecular Biology Laboratory, Grenoble Outstation, 71 Avenue des Martyrs, CS 90181, 38042 Grenoble, France; Unit for Virus Host Cell Interactions, Université Grenoble Alpes-EMBL-CNRS, 71 Avenue des Martyrs, CS 90181, 38042 Grenoble, France.
authors.forename: Erika
authors.initials: E
authors.lastname: Pellegrini
authors.affiliation: IAB, Team Host-Pathogen Interactions & Immunity to Infection, INSERM U1209, CNRS UMR5309, Université Grenoble Alpes, 38700 Grenoble, France.
authors.forename: Andrés
authors.initials: A
authors.lastname: Palencia
authors.affiliation: IAB, Team Host-Pathogen Interactions & Immunity to Infection, INSERM U1209, CNRS UMR5309, Université Grenoble Alpes, 38700 Grenoble, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Braun
authors.affiliation: Structural Biology Group, European Synchrotron Radiation Facility, 71 Avenue des Martyrs, CS 90181, 38042 Grenoble, France.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Kapp
authors.affiliation: IAB, Team Host-Pathogen Interactions & Immunity to Infection, INSERM U1209, CNRS UMR5309, Université Grenoble Alpes, 38700 Grenoble, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Bougdour
authors.affiliation: European Molecular Biology Laboratory, Grenoble Outstation, 71 Avenue des Martyrs, CS 90181, 38042 Grenoble, France; Unit for Virus Host Cell Interactions, Université Grenoble Alpes-EMBL-CNRS, 71 Avenue des Martyrs, CS 90181, 38042 Grenoble, France. Electronic address: belrhali@embl.fr.
authors.forename: Hassan
authors.initials: H
authors.lastname: Belrhali
authors.affiliation: European Molecular Biology Laboratory, Grenoble Outstation, 71 Avenue des Martyrs, CS 90181, 38042 Grenoble, France; Unit for Virus Host Cell Interactions, Université Grenoble Alpes-EMBL-CNRS, 71 Avenue des Martyrs, CS 90181, 38042 Grenoble, France. Electronic address: mbowler@embl.fr.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Bowler
authors.affiliation: IAB, Team Host-Pathogen Interactions & Immunity to Infection, INSERM U1209, CNRS UMR5309, Université Grenoble Alpes, 38700 Grenoble, France. Electronic address: mohamed-ali.hakimi@univ-grenoble-alpes.fr.
authors.forename: Mohamed-Ali
authors.initials: MA
authors.lastname: Hakimi
mesh_terms: D001665:Binding Sites; D002467:Cell Nucleus / Q000378:metabolism; D006801:Humans; D064267:Intrinsically Disordered Proteins / Q000737:chemistry / Q000378:metabolism; D020935:MAP Kinase Signaling System; D048308:Mitogen-Activated Protein Kinase 14 / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D000072417:Protein Domains; D055503:Protein Multimerization; D015800:Protozoan Proteins / Q000737:chemistry* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: C093358:GRA3 protein, Toxoplasma gondii; D064267:Intrinsically Disordered Proteins; D015800:Protozoan Proteins; D011994:Recombinant Proteins; D048308:Mitogen-Activated Protein Kinase 14
keywords: GRA24; MAPK p38; Toxoplasma effector; immunity; intrinsically disordered protein