Highly Conserved Cysteines Are Involved in the Oligomerization of Occludin—Redox Dependency of the Second Extracellular Loop

Abstract

Our 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.

Junctional proteins of the blood-brain barrier: New insights into function and dysfunction

“…21,23,24 Occludin has ability to cis-oligomerize via a MARVEL motif and to establish interaction with claudin-5, important for the organization of claudin-5 strands. 24,25 The interaction with scaffolding proteins, ZO-1 and ZO-2 as well F-actin, is important for incorporation in the TJ complex. 20,22 The third group of transmembrane TJ proteins comprises the junctional adhesion molecules (JAMs) -A, -B, -C and ESAM.…”

Redox Regulation of Cell Contacts by Tricellulin and Occludin: Redox-Sensitive Cysteine Sites in Tricellulin Regulate Both Tri- and Bicellular Junctions in Tissue Barriers as Shown in Hypoxia and Ischemia

“…A 2-Cys motif in the ECL2 forms an intraloop disulfide bridge and is involved in homophilic cis-/trans-interactions. The ECL2 structure and function are also redox sensitive (2). Occl is multiphosphorylated and thought to be relevant to regulation [reviewed in Doerfel and Huber (10)].…”

“…Clds are less sensitive to oxidative stress (14). Cell barriers and Occl oligomerization respond to reducing conditions, such as hypoxia and ischemia, or antioxidative intervention (2,24). The impairment within TJs may have dramatic consequences for the function of the respective tissues.…”

“…However, Tric and Occl share the 2-Cys motif in the ECL2, forming a redox-sensitive structure in Occl that influences cell-cell contacts (2). We therefore hypothesized that Tric provides a similar function for tricellular cell-cell contacts.…”

Dietary nitrite induces occludin nitration in the stomach

“…[16] As such, tight junctions function as gatekeepers of the paracellular pathway. [17] Although several tight junction proteins (occludin, claudin, ZO-1) have been shown to be redox sensitive, [18][19][20] here we demonstrate that occludin nitration in the gastric epithelial lining might be induced by dietary physiological concentrations of nitrite. Occludin is a tetraspan protein with two extracellular loops and three cytoplasmic domains.…”