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

Patel, Vinood B.; Lee, Christopher; El Hindy, Maya; Hezwani, Mohammed; Corry, David; Hull, Jonathon; El Amraoui, Farah; Harris, Matthew; Forshaw, Thomas; Wilson, Andrew; Mansbridge, Abbe; Hassler, Martin; Kehoe, Patrick Gavin; Love, Seth; Conway, Myra E.

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


Vinood B. Patel

Christopher Lee

Maya El Hindy

Mohammed Hezwani

David Corry

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Jonathon Hull
Senior Lecturer in Biomedical Sci (Biochemistry)

Farah El Amraoui

Matthew Harris

Thomas Forshaw

Andrew Wilson

Abbe Mansbridge

Martin Hassler

Patrick Gavin Kehoe

Seth Love

Myra Conway
Occasional Associate Lecturer - CHSS - DAS


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. © 2014 Mary Ann Liebert, Inc.

Journal Article Type Article
Acceptance Date Oct 5, 2013
Publication Date Jun 1, 2014
Deposit Date Nov 18, 2013
Publicly Available Date Jan 17, 2018
Journal Antioxidants and Redox Signaling
Print ISSN 1523-0864
Electronic ISSN 1557-7716
Publisher Mary Ann Liebert
Peer Reviewed Not Peer Reviewed
Volume 20
Issue 16
Pages 2497-2513
Keywords branched-chain, aminotransferase proteins, redox, disulfide, isomerase, Alzheimer's disease
Public URL
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Additional Information Additional Information : This is a copy of an article published in Antioxidants & Redox Signaling © [2014] [copyright Mary Ann Liebert, Inc.]; Antioxidants & Redox Signaling is available online at:
Contract Date Jan 17, 2018


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