Evolution and inhibition of the FIKK effector kinase family inP. falciparum

Abstract

AbstractAmong the ∼200Plasmodiumspecies that infect vertebrates, six infect humans. Of these,P. falciparumcauses >95% of all ∼500,000 annual fatalities. Phylogenetically,P. falciparumbelongs to theLaveraniasubgenus, a group ofPlasmodiumspecies that infect great apes. Common toLaveraniaspecies is the family of FIKK kinases. One million years ago, a single FIKK kinase conserved in allPlasmodiumspecies gained an export element in theLaveraniasubgenus and expanded into the family of ∼20 atypical FIKK kinases, most of which are exported into the host cell. Thefikkgenes are conserved in syntenic loci across theLaverania, arguing for a rapid expansion controlling important functions in host cell remodelling and pathogenesis. We provide evidence that the FIKK paralogues evolved specific and mutually exclusive phosphorylation motif preferences, conserved across theirLaveraniaorthologues, in a short evolutionary timeframe. Surprisingly, we find that FIKK13 has evolved exclusive tyrosine-phosphorylation preference, which was thought to be absent inPlasmodiumspecies. Combining a crystal structure with AlphaFold2 predictions, we identify residues that determine kinase-specificity within the FIKK family in a fast-evolving flexible loop. Finally, we show that all expressed members of the FIKK kinase family can be chemically inhibitedin vitrousing a single compound. Such a pan-specific inhibitor of this kinase family important for virulence could reduce the ability of the parasite to gain escape-mutations and resistance.