Structural basis for the role of sorting nexins in host cell invasion by Chlamydia trachomatis

B Paul, M Kerr, R Teasdale and B Collins

Institute for molecular Bioscience, University of Queensland, Brisbane, Australia

Sorting nexins (SNX) are a large and diverse group of endosomal-associated proteins that are involved in a variety of functions, including endosomal sorting and cell signaling. The best-studied subfamily of SNX proteins is the SNX-BAR subfamily, which are comprised of an N-terminal phosphoinositide binding PX domain, and a C-terminal BAR domain that promotes membrane curvature leading to membrane tubulation. One of the major functions of SNX-BAR proteins is tubular-based endosomal sorting from endosome to the trans-Golgi-network (TGN), and this process is tightly coupled with a trimeric protein complex called 'retromer'. Recently, members of the SNX-BAR family were found to be hijacked by the bacterial pathogen Chlamydia trachomatis, and were recruited to the surrounding membrane of the large vacuole called the chlamydial inclusion. Chlamydia secretes a host of so called inclusion proteins or 'Incs' via a type III secretion system that decorate the surrounding inclusion membrane. One of these proteins, inclusion membrane protein E (IncE), sequesters the SNX-BAR proteins SNX5, SNX6 and SNX32 by directly binding their PX domains via a short peptide sequence. We have determined the structure of the SNX5-IncE host-pathogen protein complex at high resolution using X-ray crystallography, and find that an extended IncE sequence forms a long β-hairpin structure that binds with high affinity to a conserved surface of the SNX5 PX domain. This work provides the first structural insights into the function of the numerous chlamydial inclusion proteins required for host infection, and also the first example of how PX domains can regulate not only lipid interactions but also protein-protein association.