FIGURE 8.

Model for efficient oxidative protein folding in mammalian ER functioned by interplay between Ero1α and PDIs. At steady states, Ero1α in the ER lumen is predominantly in the inactive states, and PDIs oxidoreductases are present in a balanced reduced (blue) and oxidized (red) distribution (only the catalytic domain is shown for simplicity). Once the loading of reduced nascent substrates explodes, the redox homeostasis in the ER will be disturbed, and reduced substrates as well as increased GSH generate more reduced PDIs. These reduced PDIs quickly reduce the regulatory disulfides (Cys94-Cys131 and Cys99-Cys104) of Ero1α, and liberate the outer active site located in the loop region (green arrow, right). The activated Ero1α specifically recognizes the b′-a′ domains of PDI and preferentially oxidizes the active site in the a′ domain, which further introduces disulfides into reduced substrates and GSH (red arrows). The asymmetric oxidation of PDI by Ero1α keeps the a domain in reduced state, which functions to catalyze efficient disulfide isomerization for the production of correctly folded substrates with complicated disulfides (blue arrow). Once the thiol-disulfide equilibrium in the ER is reestablished, the regulatory disulfides of Ero1α are easily re-formed either by self-oxidation or facilitated by oxidized PDIs to decrease the flow of oxidizing power into ER and avoid the futile oxidation cycles (green arrow, left).