Allosteric regulation and enzymatic mechanism of YopJ family of bacterial effectors

Abstract

Bacterial effectors secreted by the type III secretion system manipulate host signaling pathways to promote bacterial pathogenesis. The Yersinia outer protein J (YopJ) family of effectors, found in diverse plant and animal bacterial pathogens, represent a novel class of acetyltransferases that modify cellular proteins to suppress host defense. Distinct from other acetyltransferases, YopJ family of acetyltransferases modifies target proteins through a cysteine protease‐like catalytic core, which is further regulated by inositol hexakisphosphate (IP6), a eukaryote‐specific ligand. However, the substrate recognition and catalytic mechanism of these enzymes have not been well understood. Through structural and biochemical analyses, we demonstrate that both formation of the acetyl‐CoA binding pocket and substrate binding of YopJ effector is allosterically regulated by the IP6‐induced structural rearrangements. Furthermore, we present evidence that YopJ effector employs a “ping‐pong” route of catalysis involving formation of an “acetyl‐cysteine” intermediate. Together, our study sets the structure‐function paradigm for a novel class of acetyltransferases and a conserved regulatory mechanism of YopJ effectors.