Structure, mechanism, and evolution of Ero1 family enzymes.

SIGNIFICANCE

Disulfide bond formation is an essential reaction involved in the folding and maturation of many secreted and membrane proteins. Both prokaryotic and eukaryotic cells utilize various disulfide oxidoreductases and redox-active cofactors to accelerate this oxidative reaction, and higher eukaryotes have diversified and refined these disulfide-introducing cascades over the course of evolution.

RECENT ADVANCES

In the past decade, atomic resolution structures have been solved for an increasing number of disulfide oxidoreductases, thereby revealing the structural and mechanistic basis of cellular disulfide bond formation systems.

CRITICAL ISSUES

In this review, we focus on the evolution, structure, and regulatory mechanisms of endoplasmic reticulum oxidoreductin 1 (Ero1) family enzymes, the primary disulfide bond-generating catalysts in the endoplasmic reticulum (ER). Detailed comparison of Ero1 with other oxidoreductases, such as Prx4, QSOX, Erv1/2, and disulfide bond protein B (DsbB), provides important insight into how this ER-resident flavoenzyme acts in a regulated and specific manner to maintain redox and protein homeostasis in eukaryotic cells.

FUTURE DIRECTIONS

Currently, it is presumed that multiple pathways in addition to that mediated by Ero1 cooperate to achieve oxidative folding of many secretory and membrane proteins in mammalian cells. The important open question is how each oxidative pathway works distinctly or redundantly in response to various cellular conditions.