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Structure. 2017 Jan 3;25(1):16-26. doi: 10.1016/j.str.2016.10.011. Epub 2016 Nov 23.

Structural Basis for the Subversion of MAP Kinase Signaling by an Intrinsically Disordered Parasite Secreted Agonist.

Author information

1
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.
2
IAB, Team Host-Pathogen Interactions & Immunity to Infection, INSERM U1209, CNRS UMR5309, Université Grenoble Alpes, 38700 Grenoble, France.
3
Structural Biology Group, European Synchrotron Radiation Facility, 71 Avenue des Martyrs, CS 90181, 38042 Grenoble, France.
4
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.
5
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.
6
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.

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.

KEYWORDS:

GRA24; MAPK p38; Toxoplasma effector; immunity; intrinsically disordered protein

PMID:
27889209
PMCID:
PMC5222587
DOI:
10.1016/j.str.2016.10.011
[Indexed for MEDLINE]
Free PMC Article

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