Molecular Mechanisms Regulating Oxidative Activity of the Ero1 Family in the Endoplasmic Reticulum

Abstract

Formation of disulfide bonds in the endoplasmic reticulum (ER) is catalyzed by the ER oxidoreductin (Ero1) family of sulfhydryl oxidases. Ero1 oxidizes protein disulfide isomerase (PDI), which, in turn, introduces disulfides into ER client proteins. To maintain an oxidized state, Ero1 couples disulfide transfer to PDI with reduction of molecular oxygen, forming hydrogen peroxide. Thus, Ero1 activity constitutes a potential source of ER-derived oxidative stress. Intricate feedback mechanisms have evolved to prevent Ero1 hyperactivity. Central to these mechanisms are noncatalytic cysteines, which form regulatory disulfides and influence catalytic activity of Ero1 in relation to local redox conditions. Here we focus on the distinct regulatory disulfides modulating Ero1 activities in the yeast and mammalian ER. In addition to considering effects on the Ero1 catalytic cycle, we consider the implications of these mechanisms with regard to function of Ero1 isoforms and the roles of Ero1 during responses to ER stress.