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

• Published in: Structure (London) 2017-01, Vol.25 (1), p.16-26
• Main Authors: Pellegrini, Erika, Palencia, Andrés, Braun, Laurence, Kapp, Ulrike, Bougdour, Alexandre, Belrhali, Hassan, Bowler, Matthew W., Hakimi, Mohamed-Ali
• Format: Article
• Language: English
• Subjects: Binding Sites; Cell Nucleus - metabolism; GRA24; Humans; immunity; intrinsically disordered protein; Intrinsically Disordered Proteins - chemistry; Intrinsically Disordered Proteins - metabolism; Life Sciences; MAP Kinase Signaling System; MAPK p38; Mitogen-Activated Protein Kinase 14 - chemistry; Mitogen-Activated Protein Kinase 14 - metabolism; Models, Molecular; Protein Binding; Protein Conformation; Protein Domains; Protein Multimerization; Protozoan Proteins - chemistry; Protozoan Proteins - metabolism; Recombinant Proteins - chemistry; Recombinant Proteins - metabolism; Toxoplasma effector
• ISSN: 0969-2126; 1878-4186; 1878-4186
• DOI: 10.1016/j.str.2016.10.011

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. [Display omitted] •Toxoplasmosis controls its host immune response via a protein effector, GRA24•A recombinant complex of GRA24 and MAPK p38α demonstrates how the protein works•An adapted KIM domain ensures activation and a sustained inflammatory response•The recombinant complex is useful in the evaluation of p38 inhibitors Pellegrini et al. show how a protein, GRA24, secreted by the causative agent of toxoplasmosis, directly activates a host MAP kinase signaling cascade (p38α). The structure of the complex provides a mechanistic view of activation and defines GRA24 as the only component required to activate p38α.