Role of TM3 in claudin-15 strand flexibility: A molecular dynamics study
Claudins are cell-cell adhesion proteins within tight junctions that connect epithelial cells together. Claudins polymerize into a network of strand-like structures within the membrane of adjoining cells and create ion channels that control paracellular permeability to water and small molecules. Tig...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-09-01
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| Series: | Frontiers in Molecular Biosciences |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmolb.2022.964877/full |
| _version_ | 1811258126682292224 |
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| author | Shadi Fuladi Sarah McGuinness Fatemeh Khalili-Araghi |
| author_facet | Shadi Fuladi Sarah McGuinness Fatemeh Khalili-Araghi |
| author_sort | Shadi Fuladi |
| collection | DOAJ |
| description | Claudins are cell-cell adhesion proteins within tight junctions that connect epithelial cells together. Claudins polymerize into a network of strand-like structures within the membrane of adjoining cells and create ion channels that control paracellular permeability to water and small molecules. Tight junction morphology and barrier function is tissue specific and regulated by claudin subtypes. Here, we present a molecular dynamics study of claudin-15 strands within lipid membranes and the role of a single-point mutation (A134P) on the third transmembrane helix (TM3) of claudin-15 in determining the morphology of the strand. Our results indicate that the A134P mutation significantly affects the lateral flexibility of the strands, increasing the persistence length of claudin-15 strands by a factor of three. Analyses of claudin-claudin contact in our μsecond-long trajectories show that the mutation does not alter the intermolecular contacts (interfaces) between claudins. However, the dynamics and frequency of interfacial contacts are significantly affected. The A134P mutation introduces a kink in TM3 of claudin-15 similar to the one observed in claudin-3 crystal structure. The kink on TM3 skews the rotational flexibility of the claudins in the strands and limits their fluctuation in one direction. This asymmetric movement in the context of the double rows reduces the lateral flexibility of the strand and leads to higher persistence lengths of the mutant. |
| first_indexed | 2024-04-12T18:08:22Z |
| format | Article |
| id | doaj.art-a2453bf272a54d19b4abc1a8564af507 |
| institution | Directory Open Access Journal |
| issn | 2296-889X |
| language | English |
| last_indexed | 2024-04-12T18:08:22Z |
| publishDate | 2022-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Biosciences |
| spelling | doaj.art-a2453bf272a54d19b4abc1a8564af5072022-12-22T03:21:55ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2022-09-01910.3389/fmolb.2022.964877964877Role of TM3 in claudin-15 strand flexibility: A molecular dynamics studyShadi Fuladi0Sarah McGuinness1Fatemeh Khalili-Araghi2Department of Physics, University of Illinois at Chicago, Chicago, IL, United StatesDepartment of Bioengineering, University of Illinois at Chicago, Chicago, IL, United StatesDepartment of Physics, University of Illinois at Chicago, Chicago, IL, United StatesClaudins are cell-cell adhesion proteins within tight junctions that connect epithelial cells together. Claudins polymerize into a network of strand-like structures within the membrane of adjoining cells and create ion channels that control paracellular permeability to water and small molecules. Tight junction morphology and barrier function is tissue specific and regulated by claudin subtypes. Here, we present a molecular dynamics study of claudin-15 strands within lipid membranes and the role of a single-point mutation (A134P) on the third transmembrane helix (TM3) of claudin-15 in determining the morphology of the strand. Our results indicate that the A134P mutation significantly affects the lateral flexibility of the strands, increasing the persistence length of claudin-15 strands by a factor of three. Analyses of claudin-claudin contact in our μsecond-long trajectories show that the mutation does not alter the intermolecular contacts (interfaces) between claudins. However, the dynamics and frequency of interfacial contacts are significantly affected. The A134P mutation introduces a kink in TM3 of claudin-15 similar to the one observed in claudin-3 crystal structure. The kink on TM3 skews the rotational flexibility of the claudins in the strands and limits their fluctuation in one direction. This asymmetric movement in the context of the double rows reduces the lateral flexibility of the strand and leads to higher persistence lengths of the mutant.https://www.frontiersin.org/articles/10.3389/fmolb.2022.964877/fulltight junctions (TJ)claudin-15ion channelsmolecular dynamicsmolecular mechanics |
| spellingShingle | Shadi Fuladi Sarah McGuinness Fatemeh Khalili-Araghi Role of TM3 in claudin-15 strand flexibility: A molecular dynamics study Frontiers in Molecular Biosciences tight junctions (TJ) claudin-15 ion channels molecular dynamics molecular mechanics |
| title | Role of TM3 in claudin-15 strand flexibility: A molecular dynamics study |
| title_full | Role of TM3 in claudin-15 strand flexibility: A molecular dynamics study |
| title_fullStr | Role of TM3 in claudin-15 strand flexibility: A molecular dynamics study |
| title_full_unstemmed | Role of TM3 in claudin-15 strand flexibility: A molecular dynamics study |
| title_short | Role of TM3 in claudin-15 strand flexibility: A molecular dynamics study |
| title_sort | role of tm3 in claudin 15 strand flexibility a molecular dynamics study |
| topic | tight junctions (TJ) claudin-15 ion channels molecular dynamics molecular mechanics |
| url | https://www.frontiersin.org/articles/10.3389/fmolb.2022.964877/full |
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