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The branched-chain aminotransferase proteins: novel redox chaperones for protein disulfide isomerase--implications in Alzheimer's disease.


ABSTRACT:

Aims

The human branched-chain aminotransferase proteins (hBCATm and hBCATc) are regulated through oxidation and S-nitrosation. However, it remains unknown whether they share common redox characteristics to enzymes such as protein disulfide isomerase (PDI) in terms of regulating cellular repair and protein misfolding.

Results

Here, similar to PDI, the hBCAT proteins showed dithiol-disulfide isomerase activity that was mediated through an S-glutathionylated mechanism. Site-directed mutagenesis of the active thiols of the CXXC motif demonstrates that they are fundamental to optimal protein folding. Far Western analysis indicated that both hBCAT proteins can associate with PDI. Co-immunoprecipitation studies demonstrated that hBCATm directly binds to PDI in IMR-32 cells and the human brain. Electron and confocal microscopy validated the expression of PDI in mitochondria (using Mia40 as a mitochondrial control), where both PDI and Mia40 were found to be co-localized with hBCATm. Under conditions of oxidative stress, this interaction is decreased, suggesting that the proposed chaperone role for hBCATm may be perturbed. Moreover, immunohistochemistry studies show that PDI and hBCAT are expressed in the same neuronal and endothelial cells of the vasculature of the human brain, supporting a physiological role for this binding.

Innovation

This study identifies a novel redox role for hBCAT and confirms that hBCATm differentially binds to PDI under cellular stress.

Conclusion

These studies indicate that hBCAT may play a role in the stress response of the cell as a novel redox chaperone, which, if compromised, may result in protein misfolding, creating aggregates as a key feature in neurodegenerative conditions such as Alzheimer's disease.

SUBMITTER: El Hindy M 

PROVIDER: S-EPMC4026213 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Publications

The branched-chain aminotransferase proteins: novel redox chaperones for protein disulfide isomerase--implications in Alzheimer's disease.

El Hindy Maya M   Hezwani Mohammed M   Corry David D   Hull Jonathon J   El Amraoui Farah F   Harris Matthew M   Lee Christopher C   Forshaw Thomas T   Wilson Andrew A   Mansbridge Abbe A   Hassler Martin M   Patel Vinood B VB   Kehoe Patrick Gavin PG   Love Seth S   Conway Myra Elizabeth ME  

Antioxidants & redox signaling 20131221 16


<h4>Aims</h4>The human branched-chain aminotransferase proteins (hBCATm and hBCATc) are regulated through oxidation and S-nitrosation. However, it remains unknown whether they share common redox characteristics to enzymes such as protein disulfide isomerase (PDI) in terms of regulating cellular repair and protein misfolding.<h4>Results</h4>Here, similar to PDI, the hBCAT proteins showed dithiol-disulfide isomerase activity that was mediated through an S-glutathionylated mechanism. Site-directed  ...[more]

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