The pathogen-encoded signaling receptor Tir exploits host-like intrinsic disorder to assist infection

Abstract

The translocated intimin receptor (Tir) is a central effector of Attaching/Effacing (A/E) pathogens responsible for worldwide foodborne disease cases. Upon delivery into host cells, Tir acts as a cell-signaling receptor that rewires host cellular processes to assist infection. We found that this bacterial-encoded transmembrane protein comprises highly disordered intracellular domains bearing host-like motifs that bind host proteins. This unexpected trait was found prevalent in several other effectors secreted by A/E bacteria. We assessed Tir's intrinsic disorder by an integrative structural biophysics approach, unveiling that its intracellular side comprises a partially structured N-terminal dimer (N-Tir) and disordered C-terminal tail (C-Tir). NMR analysis revealed that C-Tir has pre-existing transient structures at phosphorylation sites, including host-like immunoreceptor tyrosine-based inhibitory motifs (ITIMs). These ITIM-like sequences were found to bind lipid bilayer as previously observed for host T-cell receptor cytoplasmic disordered domains. C-Tir membrane affinity is residue-specific and modulated by lipid composition, suggesting a regulation layer based on membrane composition. Using NMR, we also observed that the disordered C-Tir displays multisite tyrosine-phosphorylation sites that mediate promiscuous binding to the C-terminal SH2 domain of host SHP-1. Together, these novel insights provide an updated picture of Tir structural features and highlight Tir-mediated mimicry of host disordered membrane receptors as a molecular strategy for host cell subversion.