The Toxoplasma pseudokinase ROP5 is an allosteric inhibitor of the immunity-related GTPases

J Biol Chem. 2014 Oct 3;289(40):27849-58. doi: 10.1074/jbc.M114.567057. Epub 2014 Aug 12.


The Red Queen hypothesis proposes that there is an evolutionary arms race between host and pathogen. One possible example of such a phenomenon could be the recently discovered interaction between host defense proteins known as immunity-related GTPases (IRGs) and a family of rhoptry pseudokinases (ROP5) expressed by the protozoan parasite, Toxoplasma gondii. Mouse IRGs are encoded by an extensive and rapidly evolving family of over 20 genes. Similarly, the ROP5 family is highly polymorphic and consists of 4-10 genes, depending on the strain of Toxoplasma. IRGs are known to be avidly bound and functionally inactivated by ROP5 proteins, but the molecular basis of this interaction/inactivation has not previously been known. Here we show that ROP5 uses a highly polymorphic surface to bind adjacent to the nucleotide-binding domain of an IRG and that this produces a profound allosteric change in the IRG structure. This has two dramatic effects: 1) it prevents oligomerization of the IRG, and 2) it alters the orientation of two threonine residues that are targeted by the Toxoplasma Ser/Thr kinases, ROP17 and ROP18. ROP5s are highly specific in the IRGs that they will bind, and the fact that it is the most highly polymorphic surface of ROP5 that binds the IRG strongly supports the notion that these two protein families are co-evolving in a way predicted by the Red Queen hypothesis.

Keywords: Crystal Structure; GTPase; Innate Immunity; Parasitology; Protein Kinase.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation
  • Animals
  • GTP Phosphohydrolases / chemistry*
  • GTP Phosphohydrolases / genetics
  • GTP Phosphohydrolases / metabolism*
  • Host-Parasite Interactions
  • Humans
  • Mice
  • Models, Molecular
  • Phosphotransferases / chemistry
  • Phosphotransferases / genetics
  • Phosphotransferases / metabolism*
  • Protozoan Proteins / chemistry
  • Protozoan Proteins / genetics
  • Protozoan Proteins / metabolism*
  • Toxoplasma / enzymology*
  • Toxoplasma / genetics
  • Toxoplasmosis / enzymology*
  • Toxoplasmosis / genetics
  • Toxoplasmosis / parasitology


  • Protozoan Proteins
  • Phosphotransferases
  • GTP Phosphohydrolases
  • Iigp1 protein, mouse

Associated data

  • PDB/4LV5
  • PDB/4LV8