ERP57 (PDIA3) — Protein Disulfide Isomerase Family A Member 3

ERP57 (PDIA3) — Protein Disulfide Isomerase Family A Member 3

Overview

ERP57 (also known as PDIA3, Protein Disulfide Isomerase Family A Member 3, or Grp58) is a critical endoplasmic reticulum (ER) chaperone protein that plays essential roles in protein folding, disulfide bond formation, and ER stress responses. As a member of the protein disulfide isomerase (PDI) family, ERP57 catalyzes the formation and rearrangement of disulfide bonds in nascent proteins, ensuring proper protein folding and quality control within the ER lumen.

ERP57 has emerged as a significant player in the pathogenesis of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS)[@jeffries2020]. The protein's involvement in multiple disease pathways—from amyloid-beta (Aβ) metabolism and tau pathology to α-synuclein aggregation and TDP-43 proteostasis—positions it as both a therapeutic target and a potential biomarker for neurodegeneration. Importantly, ERP57 demonstrates neuroprotective properties in multiple model systems, making its upregulation a promising therapeutic strategy[@erickson2014].

ERP57 (PDIA3) — Protein Disulfide Isomerase Family A Member 3

Overview

ERP57 (also known as PDIA3, Protein Disulfide Isomerase Family A Member 3, or Grp58) is a critical endoplasmic reticulum (ER) chaperone protein that plays essential roles in protein folding, disulfide bond formation, and ER stress responses. As a member of the protein disulfide isomerase (PDI) family, ERP57 catalyzes the formation and rearrangement of disulfide bonds in nascent proteins, ensuring proper protein folding and quality control within the ER lumen.

ERP57 has emerged as a significant player in the pathogenesis of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS)[@jeffries2020]. The protein's involvement in multiple disease pathways—from amyloid-beta (Aβ) metabolism and tau pathology to α-synuclein aggregation and TDP-43 proteostasis—positions it as both a therapeutic target and a potential biomarker for neurodegeneration. Importantly, ERP57 demonstrates neuroprotective properties in multiple model systems, making its upregulation a promising therapeutic strategy[@erickson2014].

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">ERP57 (PDIA3) — Protein Disulfide Isomerase Family A Member 3</th></tr>
<tr><td><strong>Gene Symbol</strong></td><td>ERP57 / PDIA3</td></tr>
<tr><td><strong>Protein Name</strong></td><td>Protein disulfide-isomerase A3</td></tr>
<tr><td><strong>Chromosome</strong></td><td>15q15.3</td></tr>
<tr><td><strong>NCBI Gene ID</strong></td><td>[10957](https://www.ncbi.nlm.nih.gov/gene/10957)</td></tr>
<tr><td><strong>OMIM</strong></td><td>602046</td></tr>
<tr><td><strong>Ensembl ID</strong></td><td>ENSG00000123131</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>[P30101](https://www.uniprot.org/uniprot/P30101)</td></tr>
<tr><td><strong>Protein Family</strong></td><td>PDI family</td></tr>
<tr><td><strong>Subcellular Location</strong></td><td>Endoplasmic reticulum</td></tr>
<tr><td><strong>Associated Diseases</strong></td><td>AD, PD, ALS, ER Stress Disorders</td></tr>
</table>
</div>

Gene and Protein Structure

Genomic Organization

The PDIA3 gene is located on chromosome 15q15.3 and spans approximately 14 kb of genomic DNA consisting of 13 exons that encode a protein of 505 amino acids with a molecular weight of approximately 57 kDa. The gene promoter contains multiple regulatory elements including the ER stress response element (ERSE) and XBP1 binding sites, enabling transcriptional upregulation in response to ER stress[@xiao2019].

Protein Domain Architecture

ERP57 contains multiple functional domains arranged in a modular structure:

Molecular Functions

Protein Disulfide Isomerase Activity

ERP57 is a multifunctional ER resident protein with multiple enzymatic properties[@xiao2019]:

The catalytic activity depends on the C-terminal CGHC motif in domain A:

• Oxidation: Formation of disulfide bonds (reduces ER oxidizing environment)
• Reduction: Reduction of disulfide bonds (generates reduced substrates)
• Isomerization: Shuffling of disulfide bonds (corrects mispairing)

ER Quality Control

ERP57 operates as a central component of the ER quality control system[@ruggiano2014]:

• ER-associated degradation (ERAD): Facilitates recognition and retrotranslocation of misfolded proteins
• Calnexin/calreticulin partnership: Works with these ER chaperones to ensure proper glycoprotein folding[@lamriben2016]
• Redox regulation: Maintains the ER redox environment necessary for disulfide bond formation[@kosuri2018]
• Substrate recognition: Binds to diverse client proteins including APP, α-synuclein, and TDP-43

Role in Alzheimer's Disease

APP Processing and Amyloidogenesis

In AD, ERP57 demonstrates complex involvement in disease pathogenesis through multiple mechanisms[@wang2018]:

Tau Pathology

ERP57 levels are significantly altered in tauopathy brains[@huang2020]:

• Expression changes: Downregulated in AD hippocampus and cortex
• Tau phosphorylation: Modulates tau kinases and phosphatases
• Aggregation: Interacts with phosphorylated tau species
• Neurofibrillary tangles: Colocalizes with NFT pathology in some cases

Synaptic Dysfunction

ERP57 plays a critical role in maintaining synaptic function[@martinez2019]:

• ER calcium dysregulation: Contributes to synaptic calcium imbalance
• Synaptic protein folding: Essential for proper folding of synaptic proteins
• ER stress induction: Chronic ER stress leads to synaptic failure
• Neuroprotection: Up-regulation of ERP57 can protect neurons from Aβ-induced toxicity[@erickson2014]

Role in Parkinson's Disease

Alpha-Synuclein Aggregation

ERP57 plays a significant role in PD pathogenesis through direct interaction with α-synuclein[@kikuchi2020]:

• Aggregation kinetics: Modulates α-synuclein aggregation propensity
• ER quality control: Mediates ER-associated degradation of α-synuclein
• Chaperone function: Prevents toxic oligomer formation
• Secretion: Affects extracellular α-synuclein release

ER Stress and Dopaminergic Neurons

ERP57 is critically involved in ER stress-mediated dopaminergic neuron death[@kim2015]:

LRRK2 Interaction

ERP57 associates with LRRK2 mutations and modulates their pathogenic effects[@singh2019]:

• LRRK2 folding: Assists in proper LRRK2 folding in the ER
• Pathogenic mutations: Mutant LRRK2 causes ER stress that overwhelms ERP57
• Kinase activity: Modulates LRRK2 kinase function through protein-protein interactions

ER-Mitochondrial Communication

ERP57 coordinates ER-mitochondrial signaling that impacts mitochondrial quality control[@lim2019]:

• Mitochondria-associated membranes (MAMs): Localizes to ER-mitochondria contact sites
• Calcium transfer: Regulates calcium flux between ER and mitochondria
• Apoptosis: Modulates mitochondrial apoptosis pathways

Role in Amyotrophic Lateral Sclerosis

TDP-43 Pathology

In ALS, ERP57 is implicated through multiple mechanisms[@seyfert2019]:

• TDP-43 interaction: Interacts with TDP-43 and influences its aggregation in motor neurons
• Cytoplasmic inclusions: Found in TDP-43 inclusions in sporadic ALS
• Aggregate clearance: May help clear TDP-43 aggregates via ERAD

ER Stress Response

ERP57 is dysregulated in ALS motor neurons[@kikuchi2019]:

• UPR activation: High levels of ER stress in ALS motor neurons
• Adaptive failure: Impaired adaptive UPR leads to apoptosis
• Motor neuron vulnerability: Motor neurons are particularly dependent on ER quality control

Protein Homeostasis

ERP57 contributes to impaired proteostasis in ALS models[@matsumoto2019]:

• ERAD function: Impaired ERAD contributes to protein aggregate accumulation
• Mutant SOD1: Interacts with mutant SOD1 aggregates
• Proteasome dysfunction: Coordinates with UPS for protein clearance

Signaling Pathways

Unfolded Protein Response (UPR)

ERP57 is intimately involved in UPR signaling across all three major pathways[@yoshida2010][@wang2017][@adachi2018]:

IRE1 pathway:

• XBP1 activation leads to transcription of ERP57 and other ERAD components
• IRE1-mediated decay (RIDD) can degrade specific mRNAs

• eIF2α phosphorylation induces expression of ER chaperones including ERP57
• ATF4-dependent transcription of adaptive genes

• ATF6f directly activates ER chaperone genes including PDIA3
• ATF6 processing in the Golgi generates active transcription factor

Therapeutic Implications

Targeting ERP57 in Neurodegeneration

| Strategy | Approach | Status |
|----------|----------|--------|
| Up-regulation | Small molecules to increase ERP57 expression | Preclinical[@zhao2018] |
| Activity modulation | Allosteric activators of PDI activity | Preclinical[@woehlbier2019] |
| Interaction blockers | Prevent toxic protein-PDI interactions | Early stage |
| Gene therapy | AAV-mediated ERP57 delivery | Research |

Biomarker Potential

ERP57 has emerging biomarker applications:

• Cerebrospinal fluid (CSF): CSF PDIA3 levels correlate with disease progression in AD[@johansson2018]
• Blood-brain barrier: Peripheral measurement may reflect CNS ER stress
• Diagnostic utility: Combined with other ER stress markers improves diagnostic accuracy
• Progression marker: Tracks disease progression in PD and ALS

Expression Pattern

Tissue Distribution

ERP57 exhibits widespread expression:

• Brain: High expression in cortex, hippocampus, cerebellum, and substantia nigra
• Liver: High expression in hepatocytes
• Other tissues: Moderate expression in most tissues

Brain Expression

Within the brain, ERP57 shows cell-type specific patterns:

• Neurons: High expression in pyramidal neurons, dopaminergic neurons
• Astrocytes: Moderate expression, upregulated in reactive astrocytes
• Microglia: Low baseline, increased in activated states
• Oligodendrocytes: Moderate expression

Subcellular Localization

• ER lumen: Primary location (KDEL retrieval)
• Cell surface: Some cell surface expression reported
• MAMs: ER-mitochondria contact sites
• Cytoplasm: Minor cytoplasmic pool under stress conditions

Interaction Network

Key Protein Interactors

| Interactor | Interaction Type | Disease Relevance |
|------------|------------------|-----------|
| APP | Direct binding | Aβ metabolism |
| α-Synuclein | Client/chaperone | PD pathogenesis |
| TDP-43 | Complex formation | ALS pathology |
| Calnexin | Co-chaperone | Protein folding |
| Calreticulin | Co-chaperone | Protein folding |
| GRP78/BiP | Partner chaperone | ER stress response |
| LRRK2 | Protein interaction | PD pathogenesis |
| Mutant SOD1 | Aggregate binding | ALS pathology |

Cross-Links

ERP57 connects to multiple NeuroWiki pages:

• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis)
• [Unfolded Protein Response](/mechanisms/unfolded-protein-response)
• [ER Stress in Neurodegeneration](/mechanisms/er-stress-neurodegeneration)
• [ERAD Pathway](/mechanisms/endoplasmic-reticulum-associated-degradation)
• [Calnexin](/proteins/calnexin-protein)
• [Calreticulin](/proteins/calreticulin-protein)
• [GRP78/BiP](/proteins/grp78-bip-protein)

Brain Atlas Resources

• [Allen Human Brain Atlas - ERP57](https://human.brain-map.org/microarray/search/show?search_term=ERP57)
• [Allen Cell Type Atlas](https://celltypes.brain-map.org/)
• [BrainSpan Atlas of the Developing Human Brain](https://brainspan.org/)
• [Allen Mouse Brain Atlas](https://mouse.brain-map.org/)

References

Overview

ERP57 (also known as PDIA3, Protein Disulfide Isomerase Family A Member 3) is a critical endoplasmic reticulum (ER) chaperone protein that plays essential roles in protein folding, disulfide bond formation, and ER stress responses. It has emerged as a significant player in the pathogenesis of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) [1](https://pubmed.ncbi.nlm.nih.gov/32020250/).

Gene Information

<div class="infobox infobox-gene">
<div class="infobox-header">ERP57 Gene Information</div>
<div class="infobox-content">
| Property | Value |
|----------|-------|
| Gene Symbol | ERP57 / PDIA3 |
| Full Name | Protein Disulfide Isomerase Family A Member 3 |
| Chromosomal Location | 15q15.3 |
| NCBI Gene ID | [10957](https://www.ncbi.nlm.nih.gov/gene/10957) |
| OMIM | [602046](https://www.omim.org/entry/602046) |
| Ensembl ID | ENSG00000123131 |
| UniProt ID | [P30101](https://www.uniprot.org/uniprot/P30101) |
| Protein Name | Protein disulfide-isomerase A3 |
| Associated Diseases | Alzheimer's Disease, Parkinson's Disease, ALS, ER Stress Disorders |
</div>
</div>

Molecular Function

Protein Disulfide Isomerase Activity

ERP57 is a multifunctional ER resident protein with catalytic properties:

• Disulfide bond formation: Catalyzes oxidation and isomerization of disulfide bonds in nascent proteins [2](https://pubmed.ncbi.nlm.nih.gov/28731026/).
• Chaperone activity: Prevents aggregation of misfolded proteins through client binding [3](https://pubmed.ncbi.nlm.nih.gov/26019234/).
• ER calcium regulation: Modulates ER calcium storage and release [4](https://pubmed.ncbi.nlm.nih.gov/23250755/).

ER Quality Control

ERP57 operates as a central component of the ER quality control system:

• ER-associated degradation (ERAD): Facilitates recognition and retrotranslocation of misfolded proteins [5](https://pubmed.ncbi.nlm.nih.gov/24832616/).
• Calnexin/calreticulin partnership: Works with these ER chaperones to ensure proper glycoprotein folding [6](https://pubmed.ncbi.nlm.nih.gov/21930706/).
• Redox regulation: Maintains the ER redox environment necessary for disulfide bond formation [7](https://pubmed.ncbi.nlm.nih.gov/28628126/).

Role in Neurodegeneration

Alzheimer's Disease

In AD, ERP57 demonstrates complex involvement in disease pathogenesis:

• APP processing: Interacts with amyloid precursor protein (APP) and influences amyloid-beta (Aβ) generation [8](https://pubmed.ncbi.nlm.nih.gov/29753574/).
• Tau pathology: ERP57 levels are altered in tauopathy brains, suggesting involvement in tau phosphorylation and aggregation [9](https://pubmed.ncbi.nlm.nih.gov/33105862/).
• Synaptic dysfunction: Contributes to synaptic failure through ER stress induction and calcium dysregulation [10](https://pubmed.ncbi.nlm.nih.gov/31658700/).
• Neuroprotective potential: Up-regulation of ERP57 can protect neurons from Aβ-induced toxicity [11](https://pubmed.ncbi.nlm.nih.gov/25387542/).

Parkinson's Disease

ERP57 plays a significant role in PD pathogenesis through multiple mechanisms:

• α-Synuclein aggregation: Interacts with α-synuclein and influences its aggregation kinetics [12](https://pubmed.ncbi.nlm.nih.gov/30048257/).
• ER stress activation: Contributes to dopaminergic neuron death through PERK and IRE1 pathway activation [13](https://pubmed.ncbi.nlm.nih.gov/25556533/).
• Mitochondrial dysfunction: Coordinates ER-mitochondrial signaling that impacts mitochondrial quality control [14](https://pubmed.ncbi.nlm.nih.gov/29486314/).
• LRRK2 interaction: Associates with LRRK2 mutations and modulates their pathogenic effects [15](https://pubmed.ncbi.nlm.nih.gov/28988923/).

Amyotrophic Lateral Sclerosis (ALS)

In ALS, ERP57 is implicated through:

• TDP-43 pathology: Interacts with TDP-43 and influences its aggregation in motor neurons [16](https://pubmed.ncbi.nlm.nih.gov/30922732/).
• ER stress response: High levels of ER stress in ALS motor neurons involve ERP57 dysregulation [17](https://pubmed.ncbi.nlm.nih.gov/30658662/).
• Protein homeostasis: Contributes to impaired proteostasis in ALS models [18](https://pubmed.ncbi.nlm.nih.gov/31551214/).

Signaling Pathways

Unfolded Protein Response (UPR)

ERP57 is intimately involved in UPR signaling:

• IRE1 pathway: XBP1 activation leads to transcription of ERP57 and other ERAD components [19](https://pubmed.ncbi.nlm.nih.gov/22381587/).
• PERK pathway: eIF2alpha phosphorylation induces expression of ER chaperones including ERP57 [20](https://pubmed.ncbi.nlm.nih.gov/26709145/).
• ATF6 pathway: ATF6f directly activates ER chaperone genes [21](https://pubmed.ncbi.nlm.nih.gov/25394320/).

Therapeutic Implications

Targeting ERP57 in Neurodegeneration

| Strategy | Approach | Status | Reference |
|----------|----------|--------|-----------|
| Up-regulation | Small molecules to increase ERP57 expression | Preclinical | [25](https://pubmed.ncbi.nlm.nih.gov/29860270/) |
| Activity modulation | Allosteric activators of PDI activity | Preclinical | [26](https://pubmed.ncbi.nlm.nih.gov/31254607/) |
| Interaction blockers | Prevent toxic protein-PDI interactions | Early stage | [27](https://pubmed.ncbi.nlm.nih.gov/32443291/) |
| Gene therapy | AAV-mediated ERP57 delivery | Research | [28](https://pubmed.ncbi.nlm.nih.gov/33248576/) |

Biomarker Potential

ERP57 has emerging biomarker applications:

• Cerebrospinal fluid (CSF): CSF PDIA3 levels correlate with disease progression in AD [29](https://pubmed.ncbi.nlm.nih.gov/31204521/).
• Blood-brain barrier: Peripheral measurement may reflect CNS ER stress [30](https://pubmed.ncbi.nlm.nih.gov/32344867/).
• Diagnostic utility: Combined with other ER stress markers improves diagnostic accuracy [31](https://pubmed.ncbi.nlm.nih.gov/33481432/).

Expression Pattern

ERP57 exhibits widespread expression:

• Brain regions: High expression in cortex, hippocampus, cerebellum, and substantia nigra [32](https://pubmed.ncbi.nlm.nih.gov/30861128/).
• Cell types: Expressed in neurons, astrocytes, microglia, and oligodendrocytes.
• Subcellular localization: Primarily ER-resident, with some cell surface expression.
• Development: Constitutively expressed throughout development and aging.

Protein-Protein Interactions

Key ERP57 interactors in neurodegeneration:

| Interactor | Interaction Type | Relevance |
|------------|------------------|-----------|
| APP | Direct binding | Aβ metabolism |
| α-Synuclein | Client/chaperone | PD pathogenesis |
| TDP-43 | Complex formation | ALS pathology |
| Calnexin | Co-chaperone | Protein folding |
| Calreticulin | Co-chaperone | Protein folding |
| GRP78/BiP | Partner chaperone | ER stress response |

Research Directions

Current Focus Areas

Key Research Gaps

• Understanding cell-type-specific ERP57 functions in the brain.
• Elucidating the precise molecular mechanisms of ERP57 protection.
• Developing clinically viable ERP57 modulators.

Key Publications

Cross-links

• [ER Stress in Neurodegeneration](/mechanisms/er-stress-neurodegeneration)
• [Protein Disulfide Isomerases in AD](/mechanisms/pdi-alzheimers)
• [Unfolded Protein Response](/mechanisms/unfolded-protein-response)
• [Calcium Dysregulation in Neurodegeneration](/mechanisms/calcium-neurodegeneration)
• [Alpha-Synuclein Aggregation Mechanisms](/mechanisms/alpha-synuclein-aggregation)

See Also

• [Genes Index](/genes)
• [PDIA1 Protein](/proteins/pdia1-protein)
• [ER Quality Control Mechanisms](/mechanisms/er-quality-control)
• [Neurodegeneration Disease Pathways](/diseases/neurodegeneration)

External Links

• [NCBI Gene: PDIA3](https://www.ncbi.nlm.nih.gov/gene/10957)
• [UniProt: P30101](https://www.uniprot.org/uniprot/P30101)
• [Ensembl: ENSG00000123131](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000123131)
• [Human Protein Atlas: PDIA3](https://www.proteinatlas.org/ENSG00000123131-PDIA3)

Brain Atlas Resources

• [Allen Human Brain Atlas - ERP57](https://human.brain-map.org/microarray/search/show?search_term=ERP57)
• [Allen Cell Type Atlas](https://celltypes.brain-map.org/)
• [BrainSpan Atlas of the Developing Human Brain](https://brainspan.org/)
• [Allen Mouse Brain Atlas](https://mouse.brain-map.org/)

References

Pathway Diagram

The following diagram shows the key molecular relationships involving ERP57 (PDIA3) — Protein Disulfide Isomerase Family A Member 3 discovered through SciDEX knowledge graph analysis: