Claudins are one of the major components of tight junctions that play a key role in the formation and maintenance of the epithelial barrier function. Tight junction strands are dynamic and capable of adapting their structure in response to large-scale tissue rearrangement and cellular movement. Here, we present molecular dynamics simulations of claudin-15 strands of up to 225 nm in length in two parallel lipid membranes and characterize their mechanical properties. The persistence length of claudin-15 strands is comparable with those obtained from analyses of freeze-fracture electron microscopy. Our results indicate that lateral flexibility of claudin strands is due to an interplay of three sets of interfacial interaction networks between two antiparallel double rows of claudins in the membranes. In this model, claudins are assembled into interlocking tetrameric ion channels along the strand that slide with respect to each other as the strands curve over submicrometer-length scales. These results suggest a novel molecular mechanism underlying claudin-15 strand flexibility. It also sheds light on intermolecular interactions and their role in maintaining epithelial barrier function.
- Award ID(s):
- 1846021
- NSF-PAR ID:
- 10378854
- Date Published:
- Journal Name:
- Frontiers in Molecular Biosciences
- Volume:
- 9
- ISSN:
- 2296-889X
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Abstract Members of the claudin family impart unique paracellular selectivity to tight junctions. However, the structure–function relationship between claudin's strand architecture and the paracellular charge‐ and size‐selectivity is not well‐understood. This work examines the molecular assembly of claudin‐5, a barrier‐forming protein, and claudin‐15, a channel‐forming protein, to determine their structural and functional properties. We adopt a bottom‐up approach starting from claudin monomers to build the molecular architecture of the tight junction strands. First, we investigated the
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null (Ed.)Tight junctions form a barrier to control passive transport of ions and small molecules across epithelia and endothelia. In addition to forming a barrier, some of claudins control transport properties of tight junctions by forming charge- and size-selective ion channels. It has been suggested claudin monomers can form or incorporate into tight junction strands to form channels. Resolving the crystallographic structure of several claudins in recent years has provided an opportunity to examine structural basis of claudins in tight junctions. Computational and theoretical modeling relying on atomic description of the pore have contributed significantly to our understanding of claudin pores and paracellular transport. In this paper, we review recent computational and mathematical modeling of claudin barrier function. We focus on dynamic modeling of global epithelial barrier function as a function of claudin pores and molecular dynamics studies of claudins leading to a functional model of claudin channels.more » « less
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.3389/fmolb.2022.964877
