title: Compact conformations of human protein disulfide isomerase.
abstract: Protein disulfide isomerase (PDI) composed of four thioredoxin-like domains a, b, b', and a', is a key enzyme catalyzing oxidative protein folding in the endoplasmic reticulum. Large scale molecular dynamics simulations starting from the crystal structures of human PDI (hPDI) in the oxidized and reduced states were performed. The results indicate that hPDI adopts more compact conformations in solution than in the crystal structures, which are stabilized primarily by inter-domain interactions, including the salt bridges between domains a and b' observed for the first time. A prominent feature of the compact conformations is that the two catalytic domains a and a' can locate close enough for intra-molecular electron transfer, which was confirmed by the characterization of an intermediate with a disulfide between the two domains. Mutations, which disrupt the inter-domain interactions, lead to decreased reductase activity of hPDI. Our molecular dynamics simulations and biochemical experiments reveal the intrinsic conformational dynamics of hPDI and its biological impact.
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China; University of the Chinese Academy of Sciences, Beijing, China.
authors.forename: Shang
authors.initials: S
authors.lastname: Yang
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Wang
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China; Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Cui
authors.affiliation: Laboratory of Proteomics, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Ding
authors.affiliation: Laboratory of Proteomics, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Niu
authors.affiliation: Laboratory of Proteomics, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Fuquan
authors.initials: F
authors.lastname: Yang
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Chih-Chen
authors.initials: CC
authors.lastname: Wang
authors.affiliation: Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Jizhong
authors.initials: J
authors.lastname: Lou
mesh_terms: D001665:Binding Sites; D004789:Enzyme Activation; D006801:Humans; D056004:Molecular Dynamics Simulation; D009154:Mutation; D010084:Oxidation-Reduction; D010101:Oxygen Consumption; D011487:Protein Conformation; D019704:Protein Disulfide-Isomerases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017510:Protein Folding; D054730:Protein Interaction Domains and Motifs
chemical_list: D019704:Protein Disulfide-Isomerases
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