The Branched-Chain Aminotransferase Proteins: Novel Redox Chaperones for Protein Disulfide Isomerase-Implications in Alzheimer's Disease

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

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

16 Citations (Scopus)

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. Antioxid. Redox Signal. 20, 2497-2513.

Original languageEnglish
Pages (from-to)2497-2513
Number of pages17
JournalAntioxidants and Redox Signaling
Volume20
Issue number16
DOIs
Publication statusPublished - 1 Jun 2014

Keywords

  • ACTIVE-SITE CYSTEINE
  • HUMAN MITOCHONDRIAL
  • ENDOPLASMIC-RETICULUM
  • S-NITROSYLATION
  • RIBONUCLEASE-A
  • AMINO-ACIDS
  • NEUROTRANSMITTER METABOLISM
  • BOND FORMATION
  • UP-REGULATION
  • RAT-TISSUES

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