Abstract
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.
Highlights
Competition between pathogens and their hosts drives the evolution of molecules that give either organism an edge
We show that ROP5 uses a highly polymorphic surface to bind adjacent to the nucleotide-binding domain of an immunity-related GTPases (IRGs) and that this produces a profound allosteric change in the IRG structure
The ROP5-IRGa6 Interface Is Distal from the Protein Active Sites—Previous work demonstrated that ROP5 can physically interact with and inhibit the IRG system in vivo [9, 10, 22]
Summary
Competition between pathogens and their hosts drives the evolution of molecules that give either organism an edge. Of Microbiology and Immunology, Stanford University, Fairchild Bldg. Each strain of the parasite encodes multiple, divergent copies of the ROP5 genes [14, 15], and allelic variation is concentrated in hotspots of positive selection in the ROP5 pseudokinase domains [14] These differences are the greatest identified determinant of disease outcome between strains and are responsible for a Ͼ105-fold difference in virulence in a mouse model of disease [14, 15]. The structures reveal that ROP5 uses an unusual, polymorphic binding surface to bind IRGa6 and that ROP5 binding induces an allosteric rearrangement of the IRGa6 active site This has implications for the competition of Toxoplasma with the IRGs, which are, themselves, polymorphic in the region ROP5 recognizes
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
