Abstract
Claudins are a family of integral membrane proteins that enable epithelial cell/cell interactions by localizing to and driving the formation of tight junctions. Via claudin self-assembly within the membranes of adjoining cells, their extracellular domains interact, forming barriers to the paracellular transport of small molecules and ions. The bacterium Clostridium perfringens causes prevalent gastrointestinal disorders in mammals by employing an enterotoxin (CpE) that targets claudins. CpE binds to claudins at or near tight junctions in the gut and disrupts their barrier function, potentially by disabling their assembly or via cell signaling means—the mechanism(s) remain unclear. CpE ultimately destroys claudin-expressing cells through the formation of a cytotoxic membrane-penetrating β-barrel pore. Structures obtained by X-ray crystallography of CpE, claudins, and claudins in complex with CpE fragments have provided the structural bases of claudin and CpE functions, revealing potential mechanisms for the CpE-mediated disruption of claudin-made tight junctions. This review highlights current progress in this space—what has been discovered and what remains unknown—toward efforts to elucidate the molecular mechanism of CpE disruption of tight junction barriers. It further underscores the key insights obtained through structure that are being applied to develop CpE-based therapeutics that combat claudin-overexpressing cancers or modulate tight junction barriers.
Highlights
Introduction to Tight Junction BarriersFor metazoans, the dense packing of epithelial and endothelial cells helps to compartmentalize tissue-specific functions
Because obstruction of claudin/claudin trans interactions appeared obvious to all researchers that determined claudin/C-terminal domain of CpE barrier (cCpE) structures, each research group proposed mechanisms for tight junction disruption by Clostridium perfringens Enterotoxin (CpE) that focused on the cCpE-induced disabling of claudin cis assemblies [74,77,81]
In less than eight years, nine structures of five unique claudin subtypes have been determined by X-ray crystallographic methods, whereas no structural information existed for the 15+ years after the discovery of claudins as the structural backbone of tight junctions
Summary
The dense packing of epithelial and endothelial cells helps to compartmentalize tissue-specific functions. While tight junctions help cells adhere, their primary function is regulating the molecular transport of small molecules, solutes, and ions between cells through their paracellular spaces [3,4]. This molecular gatekeeping maintains tissue homeostasis and can be used to fine-tune the molecular properties of a given tissue or cell type. It is understood that claudins create the barriers or charge- and size-selective pores that tight junctions use to govern paracellular transport and fine-tune molecular homeostasis in tissues [3,4]. The review’s aim is to highlight the key structures and their associated insights that have advanced our understanding of claudins, CpE, and claudin/CpE interactions and to reflect on how these insights are being applied in the development of CpE-based therapeutics to treat cancer or tune tight junction barriers
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