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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; Conway, Myra E.; Kehoe, Patrick Gavin; Love, Seth

Authors

Vinood B. Patel

Christopher Lee

Maya El Hindy maya.elhindy@uwe.ac.uk

Mohammed Hezwani mo.hezwani@uwe.ac.uk

David Corry david.corry@uwe.ac.uk

Jonathon Hull Jonathon2.Hull@uwe.ac.uk
Senior Lecturer in Biomedical Sci (Biochemistry)

Farah El Amraoui

Matthew Harris matthew6.harris@uwe.ac.uk

Thomas Forshaw tom.forshaw@uwe.ac.uk

Andrew Wilson andrew11.wilson@uwe.ac.uk

Abbe Mansbridge abbe.mansbridge@uwe.ac.uk

Martin Hassler martin.hassler@uwe.ac.uk

Myra Conway Myra.Conway@uwe.ac.uk
Professor in Biomedical Sciences

Patrick Gavin Kehoe

Seth Love



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. © 2014 Mary Ann Liebert, Inc.

Journal Article Type Article
Publication Date Jun 1, 2014
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
APA6 Citation Patel, V. B., Lee, C., El Hindy, M., Hezwani, M., Corry, D., Hull, J., …Conway, M. E. (2014). The branched-chain aminotransferase proteins: Novel redox chaperones for protein disulfide isomerase-implications in Alzheimer's disease. Antioxidants and Redox Signaling, 20(16), 2497-2513. https://doi.org/10.1089/ars.2012.4869
DOI https://doi.org/10.1089/ars.2012.4869
Keywords branched-chain, aminotransferase proteins, redox, disulfide, isomerase, Alzheimer's disease
Publisher URL http://dx.doi.org/10.1089/ars.2012.4869
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: http://online.liebertpub.com

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