ArticleProceedings of the National Academy of Sciences of the United States of America2017
Structural basis of pH-dependent client binding by ERp44, a key regulator of protein secretion at the ER-Golgi interface.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 37 citations in OpenAlex.
- Zinc-mediated structural and functional regulation of ERp44 and ERGIC-53 in protein quality control.Journal of biochemistry · 2026Review
- Crosstalk of thioredoxin system and programmed cell death: from pathophysiology to novel therapy.Redox biology · 2026Review
- Zinc-redox crosstalk regulates proteostasis in the endoplasmic reticulum.Nature communications · 2026Article
- Non-Canonical, Strongly Selective Protein Disulfide Isomerases as Anticancer Therapeutic Targets.Biomolecules · 2025Review
- The Erv41-Erv46 complex serves as a retrograde receptor to retrieve misfolded secretory proteins that have escaped from the ER.Molecular biology of the cell · 2025Article
- Excessive or sustained endoplasmic reticulum stress: one of the culprits of adipocyte dysfunction in obesity.Therapeutic advances in endocrinology and metabolism · 2024Review
- Zinc homeostasis governed by Golgi-resident ZnT family members regulates ERp44-mediated proteostasis at the ER-Golgi interface.Nature communications · 2023Article
- Functional Heterogeneity of Bone Marrow Mesenchymal Stem Cell Subpopulations in Physiology and Pathology.International journal of molecular sciences · 2022Review
- Single-Cell RNA Sequencing of Bone Marrow Mesenchymal Stem Cells from the Elderly People.International journal of stem cells · 2022Article
- Renal cancer stem cell-derived sEVs impair renal function by inducing renal cell ERS and apoptosis in mice.Translational andrology and urology · 2022Article
- ERp44 is required for endocardial cushion development by regulating VEGFA secretion in myocardium.Cell proliferation · 2022Article
- Biogenesis of secretory immunoglobulin M requires intermediate non-native disulfide bonds and engagement of the protein disulfide isomerase ERp44.The EMBO journal · 2022Article
- Fluorescence Lifetime Imaging of pH along the Secretory Pathway.ACS chemical biology · 2022Article
- A virtuous cycle operated by ERp44 and ERGIC-53 guarantees proteostasis in the early secretory compartment.iScience · 2021Article
- Role of the early secretory pathway in SARS-CoV-2 infection.The Journal of cell biology · 2020Review
- Molecular dissection of the Erv41-Erv46 retrograde receptor reveals a conserved cysteine-rich region in Erv46 required for retrieval activity.Molecular biology of the cell · 2020Article
- Thioredoxin-related transmembrane protein 2 (TMX2) regulates the Ran protein gradient and importin-β-dependent nuclear cargo transport.Scientific reports · 2019Article
- Quaternary structure of α-amino-β-carboxymuconate-ϵ-semialdehyde decarboxylase (ACMSD) controls its activity.The Journal of biological chemistry · 2019Article
- Protein Quality Control in the Endoplasmic Reticulum.The protein journal · 2019Review
- LMAN1 (ERGIC-53) promotes trafficking of neuroreceptors.Biochemical and biophysical research communications · 2019Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
ERp44 retrieves some endoplasmic reticulum (ER)-resident enzymes and immature oligomers of secretory proteins from the Golgi. Association of ERp44 with its clients is regulated by pH-dependent mechanisms, but the molecular details are not fully understood. Here we report high-resolution crystal structures of human ERp44 at neutral and weakly acidic pH. These structures reveal key regions in the C-terminal tail (C tail) missing in the original crystal structure, including a regulatory histidine-rich region and a subsequent extended loop. The former region forms a short α-helix (α16), generating a histidine-clustered site (His cluster). At low pH, the three Trx-like domains of ERp44 ("a," "b," and "b'") undergo significant rearrangements, likely induced by protonation of His157 located at the interface between the a and b domains. The α16-helix is partially unwound and the extended loop is disordered in weakly acidic conditions, probably due to electrostatic repulsion between the protonated histidines in the His cluster. Molecular dynamics simulations indicated that helix unwinding enhances the flexibility of the C tail, disrupting its normal hydrogen-bonding pattern. The observed pH-dependent conformational changes significantly enlarge the positively charged regions around the client-binding site of ERp44 at low pH. Mutational analyses showed that ERp44 forms mixed disulfides with specific cysteines residing on negatively charged loop regions of Ero1α. We propose that the protonation states of the essential histidines regulate the ERp44-client interaction by altering the C-tail dynamics and surface electrostatic potential of ERp44.
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