Pathogen protein modularity enables elaborate mimicry of a host phosphatase

Pathogens produce diverse effector proteins to manipulate host cellular processes. However, how functional diversity is generated in an effector repertoire is poorly understood. Many effectors in the devastating plant pathogen Phytophthora contain tandem repeats of the “(L)WY” motif, which are structurally conserved but variable in sequences. Here, we discovered a functional module formed by a specific (L)WY-LWY combination in multiple Phytophthora effectors, which efficiently recruits the serine/threonine protein phosphatase 2A (PP2A) core enzyme in plant hosts. Crystal structure of an effector-PP2A complex shows that the (L)WY-LWY module enables hijacking of the host PP2A core enzyme to form functional holoenzymes. While sharing the PP2A-interacting module at the amino terminus, these effectors possess divergent C-terminal LWY units and regulate distinct sets of phosphoproteins in the host. Our results highlight the appropriation of an essential host phosphatase through molecular mimicry by pathogens and diversification promoted by protein modularity in an effector repertoire. [Display omitted] •Phytophthora effectors have conserved tandem repeats as functional modules•One such module efficiently hijacks the plant host PP2A core enzyme•This module is adopted in diverse effectors to form functional PP2A holoenzymes•These effectors regulate different sets of phosphoproteins to promote virulence Many plant pathogen effector proteins contain tandem repeat motifs that have evolved to mimic host proteins and engage host PP2A, a key eukaryote phosphatase, interfering with host processes for the benefit of the pathogen.