title: Protein folding drives disulfide formation.
abstract: PDI catalyzes the oxidative folding of disulfide-containing proteins. However, the sequence of reactions leading to a natively folded and oxidized protein remains unknown. Here we demonstrate a technique that enables independent measurements of disulfide formation and protein folding. We find that non-native disulfides are formed early in the folding pathway and can trigger misfolding. In contrast, a PDI domain favors native disulfides by catalyzing oxidation at a late stage of folding. We propose a model for cotranslational oxidative folding wherein PDI acts as a placeholder that is relieved by the pairing of cysteines caused by substrate folding. This general mechanism can explain how PDI catalyzes oxidative folding in a variety of structurally unrelated substrates.
authors.affiliation: Graduate Program in Biochemistry & Molecular Biophysics, Columbia University, New York, NY 10027, USA; Department of Biological Sciences, Columbia University, New York, NY 10027, USA. Electronic address: pallav@caa.columbia.edu.
authors.forename: Pallav
authors.initials: P
authors.lastname: Kosuri
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
authors.forename: Jorge
authors.initials: J
authors.lastname: Alegre-Cebollada
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Feng
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Kaplan
authors.affiliation: Facultad de Ciencias, Departamento de Química-Fisica, Universidad de Granada, 18071 Granada, Spain.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Inglés-Prieto
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
authors.forename: Carmen L
authors.initials: CL
authors.lastname: Badilla
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY 10027, USA; Department of Chemistry, Columbia University, New York, NY 10027, USA; Howard Hughes Medical Institute, Columbia University, New York, NY 10027, USA.
authors.forename: Brent R
authors.initials: BR
authors.lastname: Stockwell
authors.affiliation: Facultad de Ciencias, Departamento de Química-Fisica, Universidad de Granada, 18071 Granada, Spain.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Sanchez-Ruiz
authors.affiliation: Medical Nobel Institute for Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Arne
authors.initials: A
authors.lastname: Holmgren
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY 10027, USA. Electronic address: jfernandez@columbia.edu.
authors.forename: Julio M
authors.initials: JM
authors.lastname: Fernández
mesh_terms: D004220:Disulfides; D018625:Microscopy, Atomic Force; D008958:Models, Molecular; D010084:Oxidation-Reduction; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism*; D019704:Protein Disulfide-Isomerases / Q000378:metabolism*; D017510:Protein Folding; D011506:Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: D004220:Disulfides; D011506:Proteins; D011393:Procollagen-Proline Dioxygenase; C526497:P4HB protein, human; D019704:Protein Disulfide-Isomerases