Structural Details of Human Tuba Recruitment by InIC of Listeria monocytogenes Elucidate Bacterial Cell-Cell Spreading

The human pathogen Listeria monocytogenes is able to directly spread to neighboring cells of host tissues, a process recently linked to the virulence factor InIC. InIC targets the sixth SH3 domain (SH3-6) of human Tuba, disrupting its physiological interaction with the cytoskeletal protein N-WASP. The resulting loss of cortical actin tension may slacken the junctional membrane, allowing protrusion formation by motile Listeria. Complexes of Tuba SH3-6 with physiological partners N-WASP and Mena reveal equivalent binding modes but distinct affinities. The interaction surface of the infection complex InIC/Tuba SH3-6 is centered on phenylalanine 146 of InIC stacking upon asparagine 1569 of Tuba. Replacing Phe146 by alanine largely abrogates molecular affinity and in vivo mimics deletion of inIC. Collectively, our findings indicate that InIC hijacks Tuba through its LRR domain, blocking the peptide binding groove to prevent recruitment of its physiological partners.