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Review
. 2018 Jan;181:34-48.
doi: 10.1016/j.pharmthera.2017.07.011. Epub 2017 Jul 16.

Multifunctional Molecule ERp57: From Cancer to Neurodegenerative Diseases

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Free PMC article
Review

Multifunctional Molecule ERp57: From Cancer to Neurodegenerative Diseases

Aubryanna Hettinghouse et al. Pharmacol Ther. .
Free PMC article

Abstract

The protein disulfide isomerase (PDI) gene family is a protein family classically characterized by endoplasmic reticulum (ER) localization and isomerase and redox activity. ERp57, a prominent multifunctional member of the PDI family, is detected at various levels in multiple cellular localizations outside of the ER. ERp57 has been functionally linked to a host of physiological processes and numerous studies have demonstrated altered expression and aberrant functionality of ERp57 in association with diverse pathological states. Here, we summarize available knowledge of ERp57's functions in subcellular compartments and the roles of dysregulated ERp57 in various diseases toward an emphasis on the potential utility of therapeutic development of ERp57.

Keywords: Cancer; Clinical biomarker; ERp57/PDIA3; Immune response; Musculoskeletal system; Neurodegeneration.

Conflict of interest statement

6. Conflict of Interest statement

The authors declare that there are no conflicts of interest

Figures

Fig. 1
Fig. 1. The molecular structure of ERp57
A: ERp57 has a total 505 amino acids, and consists of 4 domains, a-b-b′-a′, together with a N-terminal signal sqeuence and QDEL C-terminal ER retention/retrieval motif. The a and a′ domains are shown in blue while b and b′ are shown in yellow. Both a and a′ domains hold a thioredoxin-like active site and each contains a redox active CGHC catalytic sequence. b and b′ domains contain binding sites for calreticulin and calnexin. The amino acid positions of these domains and sequences are indicated in the figure. B: The X-ray crystal structure of the b and b′ domains of Erp57 (Kozlov, et al., 2006) reveals a rigid asymmetrical three-dimensional structure. Each domain features four α helices that encase a central β sheet (from NCBI structure database MMDB: 41000 viewed using Cn3D).
Fig. 2
Fig. 2. Multiple binding partners and functions of ERp57
ERp57 can be localized to the ER, nucleus, cytoplasm, mitochondria and plasma membrane. In the ER, ERp57’s b-b′ domains associate with the P-domain of CRT/CLNX and ERp57 a and a′ active domains mediate the catalysis of CRT/CLNX bound substrates. The observation of ERp57-mediated isomerization and release of SV40 capsid proteins has implicated ERp57’s activity in viral infection. ERp57 also structurally stabilizes the MHC I PLC through formation of a disulphide bond between ERp57 and tapasin. ERp57 directly interacts with specific glycoproteins, including the growth factor PGRN, and is able to modulate their secretion. ER Ca2+ homeostasis is regulated by ERp57’s interactions with STIM1 and SERCA2b. ERp57 affects membrane proteins through both direct and indirect interactions. ERp57 mediates exposure of CRT on the cell surface, which is required for immunologic cell death. ERp57 acts as membrane receptor of 1α, 25(OH)2D3 to mediate rapid responses to bioactive vitamin D including Ca2+ release though PLA mediated phospholipase C activation. Downstream effects of ERp57: 1α, 25(OH)2D3 binding also include PLA2-mediated PKC driven ADAM10 translocation to the membrane where ADAM10 mediates ectodomain shedding of TNFR1. Ionic oscillations across the plasma membrane are controlled by ERp57’s stimulatory interactions with the NCC and H+K+ ATPase. ERp57 is also associated with an inhibitory effect upon internalization and degradation of EGFR, though the mechanism underlying this relationship is unclear. ERp57 is also found in STAT3 membrane rafts and cytosolic statosome complexes proposed to sequester activated STAT3, though the role(s) of these complexes is indefinite. In mitochondria, ERp57 can regulate Ca2+ uptake and apoptotic signaling though binding with the MCU and μ-calpain, respectively. Further, cytoplasmic ERp57 can interact with p53 to inhibit p53- induced MOMP and consequent apoptosis. ERp57 also promotes the formation of mTOR complexes and may participate in mTOR redox-sensing functions. ERp57 promotes RAR-α binding to ATRA and is required for the nuclear appearance of RAR-α. ERp57 is also capable of DNA binding at target sites either alone or as a member of several protein complexes. ERp57 associates with STAT3 and NF-kB protein complexes during transit from the cytoplasm to the nucleus and participates in complex-DNA binding. ERp57 also associates with a nuclear protein complex which targets to sites of modified DNA and has been implicated in early signal for repair machinery. Nuclear ERp57 can be found bound with APE/Ref-1 and participates in reductive activation of transcription factors. Conversely, ERp57 reduction of E2A proteins promotes heterodimerization and inhibits transcriptional activity.

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