3ahq
hyperactive human Ero1
Structural highlights
FunctionERO1A_HUMAN Oxidoreductase involved in disulfide bond formation in the endoplasmic reticulum. Efficiently reoxidizes P4HB/PDI, the enzyme catalyzing protein disulfide formation, in order to allow P4HB to sustain additional rounds of disulfide formation. Following P4HB reoxidation, passes its electrons to molecular oxygen via FAD, leading to the production of reactive oxygen species (ROS) in the cell. Required for the proper folding of immunoglobulins. Involved in the release of the unfolded cholera toxin from reduced P4HB/PDI in case of infection by V.cholerae, thereby playing a role in retrotranslocation of the toxin. Plays an important role in ER stress-induced, CHOP-dependent apoptosis by activating the inositol 1,4,5-trisphosphate receptor IP3R1.[1] [2] [3] [4] [5] [6] [7] Publication Abstract from PubMedIn the endoplasmic reticulum (ER) of eukaryotic cells, Ero1 flavoenzymes promote oxidative protein folding through protein disulphide isomerase (PDI), generating reactive oxygen species (hydrogen peroxide) as byproducts. Therefore, Ero1 activity must be strictly regulated to avoid futile oxidation cycles in the ER. Although regulatory mechanisms restraining Ero1alpha activity ensure that not all PDIs are oxidized, its specificity towards PDI could allow other resident oxidoreductases to remain reduced and competent to carry out isomerization and reduction of protein substrates. In this study, crystal structures of human Ero1alpha were solved in its hyperactive and inactive forms. Our findings reveal that human Ero1alpha modulates its oxidative activity by properly positioning regulatory cysteines within an intrinsically flexible loop, and by fine-tuning the electron shuttle ability of the loop through disulphide rearrangements. Specific PDI targeting is guaranteed by electrostatic and hydrophobic interactions of Ero1alpha with the PDI b'-domain through its substrate-binding pocket. These results reveal the molecular basis of the regulation and specificity of protein disulphide formation in human cells. Crystal structures of human Ero1alpha reveal the mechanisms of regulated and targeted oxidation of PDI.,Inaba K, Masui S, Iida H, Vavassori S, Sitia R, Suzuki M EMBO J. 2010 Oct 6;29(19):3330-43. Epub 2010 Sep 10. PMID:20834232[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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