Crystal structure of the ERp44-peroxiredoxin 4 complex reveals the molecular mechanisms of thiol-mediated protein retention

ERp44 controls the localization and transport of diverse proteins in the early secretorypathway. The mechanisms that allow client recognition and the source of the oxidativepower for forming inter-molecular disulfides were unknown. Here we present the firststructure of ERp44 bound to a client, peroxiredoxin 4. Our data reveal that ERp44binds the oxidized form of peroxiredoxin 4 via thiol-disulfide interchange reactions. Thestructure explains the redox-dependent recognition and characterizes the essentialnon-covalent interactions at the interface. The ERp44-Prx4 covalent complexes can bereduced by GSH and PDI family members in the endoplasmic reticulum, allowing thetwo components to recycle. This work provides novel insights into the mechanisms ofthiol-mediated protein retention and indicates the key roles of ERp44 in a novelbiochemical cycle to optimize oxidative folding and redox homeostasis.