ArticleCellular and molecular life sciences : CMLS2021
Distinct states of proinsulin misfolding in MIDY.
Article in Cellular and molecular life sciences : CMLS, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 33 citations in OpenAlex.
- Proinsulin regulators identified with CRISPR screen and in vivo mouse QTL mapping.Nature communications · 2026Article
- Unraveling C‑Peptide's Role in MIDY: A Structural Perspective.ACS omega · 2026Article
- Structural Communication Between C-Peptide and Insulin Within the Proinsulin Molecule.International journal of molecular sciences · 2026Article
- β-Cell Mitochondrial Dysfunction: Underlying Mechanisms and Potential Therapeutic Strategies.Cells · 2025Review
- Article
- Unique and conserved endoplasmic reticulum stress responses in neuroendocrine cells.bioRxiv : the preprint server for biology · 2025Article
- Diabetes mellitus and the key role of endoplasmic reticulum stress in pancreatic β cells.Nature reviews. Endocrinology · 2025Review
- The B22 Dilemma: Structural Basis for Conformational Differences in Proinsulin B-Chain Arg22 Mutants.Biomolecules · 2025Article
- Review
- Synthetic studies of the mutant proinsulin syndrome demonstrate correlation between folding efficiency and age of diabetes onset.International journal of peptide research and therapeutics · 2025Article
- Exploring proinsulin proteostasis: insights into beta cell health and diabetes.Frontiers in molecular biosciences · 2025Review
- Review
- Molecular puzzle of insulin: structural assembly pathways and their role in diabetes.Frontiers in cell and developmental biology · 2025Review
- OSGEP regulates islet β-cell function by modulating proinsulin translation and maintaining ER stress homeostasis in mice.Nature communications · 2024Article
- A metabolic redox relay supports ER proinsulin export in pancreatic islet β cells.JCI insight · 2024Article
- Bax Inhibitor-1 preserves pancreatic β-cell proteostasis by limiting proinsulin misfolding and programmed cell death.Cell death & disease · 2024Article
- Proinsulin folding and trafficking defects trigger a common pathological disturbance of endoplasmic reticulum homeostasis.Protein science : a publication of the Protein Society · 2024Article
- Mitochondrial bioenergetics, metabolism, and beyond in pancreatic β-cells and diabetes.Frontiers in molecular biosciences · 2024Review
- Synchronized proinsulin trafficking reveals delayed Golgi export accompanies β-cell secretory dysfunction in rodent models of hyperglycemia.Scientific reports · 2023Article
- Pancreatic beta cell ER export in health and diabetes.Frontiers in endocrinology · 2023Review
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
Abstract
A precondition for efficient proinsulin export from the endoplasmic reticulum (ER) is that proinsulin meets ER quality control folding requirements, including formation of the Cys(B19)-Cys(A20) "interchain" disulfide bond, facilitating formation of the Cys(B7)-Cys(A7) bridge. The third proinsulin disulfide, Cys(A6)-Cys(A11), is not required for anterograde trafficking, i.e., a "lose-A6/A11" mutant [Cys(A6), Cys(A11) both converted to Ser] is well secreted. Nevertheless, an unpaired Cys(A11) can participate in disulfide mispairings, causing ER retention of proinsulin. Among the many missense mutations causing the syndrome of Mutant INS gene-induced Diabetes of Youth (MIDY), all seem to exhibit perturbed proinsulin disulfide bond formation. Here, we have examined a series of seven MIDY mutants [including G(B8)V, Y(B26)C, L(A16)P, H(B5)D, V(B18)A, R(Cpep + 2)C, E(A4)K], six of which are essentially completely blocked in export from the ER in pancreatic β-cells. Three of these mutants, however, must disrupt the Cys(A6)-Cys(A11) pairing to expose a critical unpaired cysteine thiol perturbation of proinsulin folding and ER export, because when introduced into the proinsulin lose-A6/A11 background, these mutants exhibit native-like disulfide bonding and improved trafficking. This maneuver also ameliorates dominant-negative blockade of export of co-expressed wild-type proinsulin. A growing molecular understanding of proinsulin misfolding may permit allele-specific pharmacological targeting for some MIDY mutants.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.