Journal
DEVELOPMENTAL CELL
Volume 54, Issue 6, Pages 792-+Publisher
CELL PRESS
DOI: 10.1016/j.devcel.2020.07.022
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Funding
- Helen Wills Neuroscience Institute
- NIH [R01GM114344]
- UCSF NSF Center for Cellular Construction [DBI-1548297]
- NIH Ruth L. Kirschstein NRSA fellowship from the NIH [1F32GM115091]
- NSF-GRFP fellowship
- Berkeley Stem Cell Center's NIH Stem Cell Biological Engineering Training Program [T32GM098218]
- UC Berkeley Lloyd Scholar
- EMBO long-term fellowship [1075-2013]
- HFSP fellowship [LT000712/2014]
- Bakar Fellows Award
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In vertebrates, epithelial permeability is regulated by the tight junction (TJ) formed by specialized adhesive membrane proteins, adaptor proteins, and the actin cytoskeleton. Despite the TJ's critical physiological role, a molecular-level understanding of how TJ assembly sets the permeability of epithelial tissue is lacking. Here, we identify a 28-amino-acid sequence in the TJ adaptor protein ZO-1, which is responsible for actin binding, and show that this interaction is essential for TJ permeability. In contrast to the strong interactions at the adherens junction, we find that the affinity between ZO-1 and actin is surprisingly weak, and we propose a model based on kinetic trapping to explain how affinity could affect TJ assembly. Finally, by tuning the affinity of ZO-1 to actin, we demonstrate that epithelial monolayers can be engineered with a spectrum of permeabilities, which points to a promising target for treating transport disorders and improving drug delivery.
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