TXNDC5, a newly discovered disulfide isomerase with a key role in cell physiology and pathology

Abstract

Thioredoxin domain-containing 5 (TXNDC5) is a member of the protein disulfide isomerase family, acting as a chaperone of endoplasmic reticulum under not fully characterized conditions As a result, TXNDC5 interacts with many cell proteins, contributing to their proper folding and correct formation of disulfide bonds through its thioredoxin domains. Moreover, it can also work as an electron transfer reaction, recovering the functional isoform of other protein disulfide isomerases, replacing reduced glutathione in its role. Finally, it also acts as a cellular adapter, interacting with the N-terminal domain of adiponectin receptor. As can be inferred from all these functions, TXNDC5 plays an important role in cell physiology; therefore, dysregulation of its expression is associated with oxidative stress, cell ageing and a large range of pathologies such as arthritis, cancer, diabetes, neurodegenerative diseases, vitiligo and virus infections. Its implication in all these important diseases has made TXNDC5 a susceptible biomarker or even a potential pharmacological target.

Figure 1

Flow chart displaying the information collection process. Two different sources of data were used: Data from online bioinformatics databases and a search in PubMed. EndNote X1 (Thomson Reuters, New York, NY, USA). * Some references may appear in more than one section of the review.

Figure 2

Scheme showing TXNDC5 domains. The graphic shows the three Trx-like domains, placed between amino acids 14–95, 118–221 and 251–355 [26].

Figure 3

Current model of TXNDC5 interactions with different compounds. Panels (A) and (B) represent different angles of the docking assay using protein structure from Protein Data Bank [24]. First, many binding modes were generated by local and blind docking on the surface and in the cavities of the protein. Then, CHARMM (Chemistry at Harvard Macromolecules Mechanics) energies were estimated and most favorable energies were evaluated with FACTS (Fast Analytical Continuum Treatment of Solvation), clustered and visualized. Images show molecular coupling between TXNDC5 protein and the compounds cyclosporine A (blue), diazoside (red) and paracetamol (green). The interaction is mainly established within two domains of the protein involved in the action and its regulation [59,60].