Virulence without catalysis: How can a pseudokinase affect host cell signaling?

A hallmark of the pathogenic lifestyle is the secretion of enzymes and other effectors that dysregulate host signaling. Intriguingly, the most potent virulence locus identified in the intracellular parasite Toxoplasma gondii encodes a family of related catalytically inactive protein kinases, or pseudokinases. Toxoplasma has in its kinome among the highest percentage of pseudokinases among all sequenced organisms, and the majority of these appear to be secreted into the host cell. We posit that the pseudokinase fold represents a particularly well-suited domain for functional diversification, discuss the relevance of gene expansion at these loci, and outline potential mechanisms by which a pseudokinase might affect host signaling.