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Article of Interest: Protein disulfide-isomerase

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--mechanisms of protein folding, redox signaling, peptide binding

formation/isomerization of disulfide bonds to native conformation --> (1 drawing) (also see chaperon function)

``PDI displays oxidoreductase and isomerase activity, both of which depend on the type of substrate that binds to PDI and changes in PDI's redox state. For basic oxidative folding, the first substrate cysteine residue binds to the active site--the CXXC motif--of PDI to form an enzyme substate complex; a second substrate cysteine residue binds to the complex, whereby after subsequent catalysis, a stable disulfide bridge on the substrate is formed, leaving PDI's cysteine residues reduced. Afterwards, PDI is regenerated into its oxidized form by the ER's environment.

``Should there be misfolded proteins, PDI can establish (or reestablish) correct protein structure by way of reductase activity or isomerase activity. For the reductase method, misfolded substrate disulfide bonds are converted to reduced cysteine residues by the transfer of electrons from glutathione and NADPH. Afterwards, normal oxidative folding occurs to the correct pairs of substrate cysteine residues, leading to properly folded proteins. For the isomerase method, intramolecular rearrangement of substrate functional groups is catalyzed near the N terminus of the CXXC active site.

different hypothesis of mechanisms for oxidative folding (4 52)

different motifs/structural things (5 4)

``PDI also exhibits chaperone activity. Its b' domain aids in the binding of misfolded protein for subsequent degradation.

another drawing (6 282)

--inhibition and consequences of dysregulation

picture of structural disulfides in disease (5 6)

mechanisms of how pdi affects disease (5 10)

pdi and neurodegeneration/general (1)

``Redox dysregulation leads to increases in nitrosative stress in the ER. Such adverse changes in the normal cellular environment of susceptible cells, such as neurons, leads to nonfunctioning PDIs. More specifically, PDI can no longer fix misfolded proteins once its thiol group in its active site has a nitric monoxide group attached; as a result, accumulation of misfolded proteins occurs in neurons, which leads to neurodegenerative diseases such as Alzheimer's Disease and Parkinson's Disease.

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