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

Structure. 2016 Nov 14. pii: S0969-2126(16)30338-0. doi: 10.1016/j.str.2016.10.011. [Epub ahead of print]

Pellegrini E¹, Palencia A², Braun L², Kapp U³, Bougdour A², Belrhali H⁴, Bowler MW⁵, Hakimi MA⁶.

Author information

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.

Copyright © 2016 Elsevier Ltd. All rights reserved.

KEYWORDS:

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

PMID:

 

27889209

 

DOI:

 

10.1016/j.str.2016.10.011