ArticleAntioxidants & redox signaling2014
Highly conserved cysteines are involved in the oligomerization of occludin-redox dependency of the second extracellular loop.
Article in Antioxidants & redox signaling, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 37 citations in OpenAlex.
- Occludin-mediated barrier dysfunction and its role in cardiovascular and cerebrovascular pathogenesis.Frontiers in cardiovascular medicine · 2026Review
- Article
- Investigation into the Potential Mechanism of Radix Paeoniae Rubra Against Ischemic Stroke Based on Network Pharmacology.Nutrients · 2024Article
- Pathophysiology in Brain Arteriovenous Malformations: Focus on Endothelial Dysfunctions and Endothelial-to-Mesenchymal Transition.Biomedicines · 2024Review
- The Basic Requirement of Tight Junction Proteins in Blood-Brain Barrier Function and Their Role in Pathologies.International journal of molecular sciences · 2024Review
- Advancements in the study of acute lung injury resulting from intestinal ischemia/reperfusion.Frontiers in medicine · 2024Review
- Redox and Metabolic Regulation of Intestinal Barrier Function and Associated Disorders.International journal of molecular sciences · 2022Review
- Tight junction channel regulation by interclaudin interference.Nature communications · 2022Article
- Hypothiocyanous Acid Disrupts the Barrier Function of Brain Endothelial Cells.Antioxidants (Basel, Switzerland) · 2022Article
- Oxidative Stress and the Neurovascular Unit.Life (Basel, Switzerland) · 2021Review
- Tight junctions in the blood-brain barrier promote edema formation and infarct size in stroke - Ambivalent effects of sealing proteins.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2021Article
- Plasma Levels of Occludin and Claudin-5 in Acute Stroke Are Correlated with the Type and Location of Stroke but Not with the Neurological State of Patients-Preliminary Data.Brain sciences · 2020Article
- Hepatitis C virus infection and tight junction proteins: The ties that bind.Biochimica et biophysica acta. Biomembranes · 2020Review
- Structure, Function, and Regulation of the Blood-Brain Barrier Tight Junction in Central Nervous System Disorders.Frontiers in physiology · 2020Review
- The Blood-Brain Barrier and Its Intercellular Junctions in Age-Related Brain Disorders.International journal of molecular sciences · 2019Review
- Tight junction proteins at the blood-brain barrier: far more than claudin-5.Cellular and molecular life sciences : CMLS · 2019Article
- A novel occludin-targeting monoclonal antibody prevents hepatitis C virus infectionOncotarget · 2018Article
- ROS Signaling in the Pathogenesis of Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS).Advances in experimental medicine and biology · 2017Article
- Redox-sensitive structure and function of the first extracellular loop of the cell-cell contact protein claudin-1: lessons from molecular structure to animals.Antioxidants & redox signaling · 2015Article
- Promising approaches to circumvent the blood-brain barrier: progress, pitfalls and clinical prospects in brain cancer.Therapeutic delivery · 2015Review
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
unlabelledThe tight junction (TJ) marker occludin is a 4-transmembrane domain (TMD) protein with unclear physiological and pathological functions, interacting with other TJ proteins. It oligomerizes and is redox sensitive. However, oligomerization sites and mechanisms are unknown.
aimsTo identify hypoxia-sensitive binding sites, we investigated the consequences of amino-acid substitutions of highly conserved cysteines in human occludin, under normal and hypoxic incubations.
results(i) The extracellular loop 2 (ECL2) showed homophilic trans- and cis-association between opposing cells and along the cell membrane, respectively, caused by a loop properly folded via an intraloop disulfide bridge between the shielded C216 and C237. Hypoxia and reductants prevented the associations. (ii) C82 in TMD1 directly cis-associated without disulfide formation. (iii) C76 in TMD1 and C148 in TMD2 limited the trans-interaction; C76 also limited occludin-related paracellular tightness and changed the strand morphology of claudin-1. (iv) The diminished binding strength found after substituting C82, C216, or C237 was accompanied by increased occludin mobility in the cell membrane. INNOVATION: The data enable the first experimentally proven structural model of occludin and its homophilic interaction sites, in which the ECL2, via intraloop disulfide formation, has a central role in occludin's hypoxia-sensitive oligomerization and to regulate the structure of TJs.
conclusionOur findings support the new concept that occludin acts as a hypoxiasensor and contributes toward regulating the TJ assembly redox dependently. This is of pathogenic relevance for tissue barrier injury with reducing conditions. The ECL2 disulfide might be a model for four TMD proteins in TJs with two conserved cysteines in an ECL.
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