Fig. 7: A chlamydial effector exploits structural and functional mimicry to manipulate the host endocytic machinery.
The Cpn elementary body (EB) secrets SemD into the host cell, which binds to the inner leaflet of the plasma membrane. There, SemD recruits, binds and activates N-WASP by structurally and functionally mimicking the Cdc42GTP activation mechanism. SemD interacts with the C-terminal, positively charged amino acids of the N-WASP BR domain and further, the CRIB domain binds into the SemD binding groove. This then leads to the release of N-WASP from its auto-inhibited state. SemD also binds to the SNX9-SH3 domain, which brings the SNX9-BAR domain closer to the membrane. This in turn induces membrane deformation and eventually leads to closure of the matured endocytic vesicle. Due to the arrangement of the individual binding domains, which are connected by flexible linker regions, the binding sites can be freely oriented in 3D space, thus minimising steric hindrance. This can explain why SemD is postulated to be capable of binding simultaneously to the PM, SNX9 and N-WASP in vivo and hijacking their functions to promote the growth and maturation of the endocytic vesicle.
