Dataset Information

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 p38? (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 p38? 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 p38? inhibitors that have advanced to clinical trials, as it provides a hitherto unavailable stable and highly active form of p38?.

SUBMITTER: Pellegrini E

PROVIDER: S-EPMC5222587 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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

Pellegrini Erika E Palencia Andrés A Braun Laurence L Kapp Ulrike U Bougdour Alexandre A Belrhali Hassan H Bowler Matthew W MW Hakimi Mohamed-Ali MA

Structure (London, England : 1993) 20161123 1

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. ...[more]

PMID: 27889209

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Project description:CK2, a serine/threonine (Ser/Thr) kinase present in eukaryotic cells, is known to have a vast number of substrates. We have recently shown that it localizes to nuclei and at pores between hyphal compartments in Magnaporthe oryzae We performed a pulldown proteomics analysis of M. oryzae CK2 catalytic subunit MoCKa to detect interacting proteins. The MoCKa pulldown was enriched for septum and nucleolus proteins and intrinsically disordered proteins (IDPs) containing a CK2 phosphorylation motif that is proposed to destabilize and unfold α-helices. This points to a function for CK2 phosphorylation and corresponding phosphatase dephosphorylation in the formation of functional protein-protein aggregates and protein-RNA/DNA binding. To test this as widely as possible, we used secondary data downloaded from databases from a large range of M. oryzae experiments, as well as data for a relatively closely related plant-pathogenic fungus, Fusarium graminearum We found that CKa expression was strongly positively correlated with Ser/Thr phosphatases, as well as with disaggregases (HSP104, YDJ1, and SSA1) and an autophagy-indicating protein (ATG8). The latter points to increased protein aggregate formation at high levels of CKa expression. Our results suggest a general role for CK2 in chaperoning aggregation and disaggregation of IDPs and their binding to proteins, DNA, and RNA.IMPORTANCE CK2 is a eukaryotic conserved kinase enzyme complex that phosphorylates proteins. CK2 is known to phosphorylate a large number of proteins and is constitutively active, and thus a "normal" role for a kinase in a signaling cascade might not be the case for CK2. Previous results on localization and indications from the literature point to a function for CK2 phosphorylation in shaping and folding of proteins, especially intrinsically disordered proteins, which constitute about 30% of eukaryotic proteins. We used pulldown of interacting proteins and data downloaded from a large range of transcriptomic experiments in M. oryzae and complemented these with data downloaded from a large range of transcriptomic experiments in Fusarium graminearum We found support for a general role for CK2 in aggregation and disaggregation of IDPs and their binding to proteins, DNA, and RNA-interactions that could explain the importance of CK2 in eukaryotic cell function and disease.

Dataset Information

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

Publications

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

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