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.
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