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Inactivation of mammalian Ero1α is catalysed by specific protein disulfide-isomerases

Lookup NU author(s): Dr Colin Shepherd

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Abstract

Disulfide formation within the endoplasmic reticulum is a complex process requiring a disulfide exchange protein such as protein disulfide isomerase and a mechanism to form disulfides de novo. In mammalian cells, the major pathway for de novo disulfide formation involves the enzyme Ero1α which couples oxidation of thiols to the reduction of molecular oxygen to form hydrogen peroxide. Ero1α activity is tightly regulated by a mechanism that requires the formation of regulatory disulfides. These regulatory disulfides are reduced to activate and reform to inactive the enzyme. To investigate the mechanism of inactivation we analysed regulatory disulfide formation in the presence of various oxidants under controlled oxygen concentration. Neither molecular oxygen, nor hydrogen peroxide was able to oxidise Ero1α efficiently to form the correct regulatory disulfides. However, specific members of the PDI family such as PDI or ERp46 were able to catalyse this process. Further studies showed that both active sites of PDI contribute to the formation of regulatory disulfides in Ero1α and that the PDI substrate binding domain is crucial to allow electron transfer between the two enzymes. These results demonstrate a simple feedback mechanism of regulation of mammalian Ero1α involving its primary substrate.

Publication metadata

Author(s): Shepherd C, Oka OBV, Bulleid NJ

Publication type: Article

Publication status: Published

Journal: Biochemical Journal

Year: 2014

Volume: 461

Pages: 107-113

Print publication date: 23/04/2014

ISSN (print): 0264-6021

ISSN (electronic): 1470-8728

Publisher: Portland Press

URL: http://dx.doi.org/10.1042/BJ20140234

DOI: 10.1042/BJ20140234

PubMed id: 24758166

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