title: Different interaction modes for protein-disulfide isomerase (PDI) as an efficient regulator and a specific substrate of endoplasmic reticulum oxidoreductin-1α (Ero1α).
abstract: Protein-disulfide isomerase (PDI) and sulfhydryl oxidase endoplasmic reticulum oxidoreductin-1α (Ero1α) constitute the pivotal pathway for oxidative protein folding in the mammalian endoplasmic reticulum (ER). Ero1α oxidizes PDI to introduce disulfides into substrates, and PDI can feedback-regulate Ero1α activity. Here, we show the regulatory disulfide of Ero1α responds to the redox fluctuation in ER very sensitively, relying on the availability of redox active PDI. The regulation of Ero1α is rapidly facilitated by either a or a' catalytic domain of PDI, independent of the substrate binding domain. On the other hand, activated Ero1α specifically binds to PDI via hydrophobic interactions and preferentially catalyzes the oxidation of domain a'. This asymmetry ensures PDI to function simultaneously as an oxidoreductase and an isomerase. In addition, several PDI family members are also characterized to be potent regulators of Ero1α. The novel modes for PDI as a competent regulator and a specific substrate of Ero1α govern efficient and faithful oxidative protein folding and maintain the ER redox homeostasis.
authors.affiliation: From the National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China and University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Lihui
authors.initials: L
authors.lastname: Zhang
authors.affiliation: From the National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China and University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Yingbo
authors.initials: Y
authors.lastname: Niu
authors.affiliation: From the National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China and University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
authors.affiliation: From the National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China and University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Jingqi
authors.initials: J
authors.lastname: Fang
authors.affiliation: From the National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China and.
authors.forename: Xi'e
authors.initials: X
authors.lastname: Wang
authors.affiliation: From the National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China and wanglei@moon.ibp.ac.cn.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: From the National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China and chihwang@sun5.ibp.ac.cn.
authors.forename: Chih-chen
authors.initials: CC
authors.lastname: Wang
mesh_terms: D020134:Catalytic Domain; D003545:Cysteine / Q000737:chemistry; D004220:Disulfides / Q000737:chemistry; D004721:Endoplasmic Reticulum / Q000201:enzymology*; D006367:HeLa Cells; D006706:Homeostasis; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D011485:Protein Binding; D019704:Protein Disulfide-Isomerases / Q000378:metabolism*; D017510:Protein Folding; D034622:RNA Interference; D013379:Substrate Specificity
chemical_list: D004220:Disulfides; D008562:Membrane Glycoproteins; C405327:ERO1A protein, human; D010088:Oxidoreductases; D019704:Protein Disulfide-Isomerases; D003545:Cysteine; D010100:Oxygen
keywords: Disulfide; Endoplasmic Reticulum (ER); Ero1α; Oxidative Protein Folding; Protein-disulfide Isomerase; Redox Regulation; Substrate Specificity