Sorting of cadherin-catenin-associated proteins into individual clusters

The cytoplasmic tails of classical cadherins form a multiprotein cadherin-catenin complex (CCC) that constitutes the major structural unit of adherens junctions (AJs). The CCC in AJs forms junctional clusters, "E clusters," driven by and interactions in the cadherin ectodomain and stabiliz...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2021-07, Vol.118 (29), p.1
Main Authors: Troyanovsky, Regina B, Sergeeva, Alina P, Indra, Indrajyoti, Chen, Chi-Shuo, Kato, Rei, Shapiro, Lawrence, Honig, Barry, Troyanovsky, Sergey M
Format: Article
Language:English
Subjects:
Actin
Actins - metabolism
Adaptor Proteins, Signal Transducing - metabolism
Adherens junctions
Adherens Junctions - metabolism
Antibodies, Monoclonal - metabolism
Biological Sciences
Cadherins - metabolism
Catenins - metabolism
Cell Adhesion
Cell Line
Clustering
Crosslinking
E-cadherin
Green Fluorescent Proteins - metabolism
Humans
Mass spectrometry
Mass spectroscopy
Membrane Proteins - metabolism
Models, Molecular
Monoclonal antibodies
Mutation - genetics
Protein Binding
Protein Transport
Proteins
Tumor Suppressor Proteins - metabolism
Vinculin
α-Catenin
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Summary:The cytoplasmic tails of classical cadherins form a multiprotein cadherin-catenin complex (CCC) that constitutes the major structural unit of adherens junctions (AJs). The CCC in AJs forms junctional clusters, "E clusters," driven by and interactions in the cadherin ectodomain and stabilized by α-catenin-actin interactions. Additional proteins are known to bind to the cytoplasmic region of the CCC. Here, we analyze how these CCC-associated proteins (CAPs) integrate into cadherin clusters and how they affect the clustering process. Using a cross-linking approach coupled with mass spectrometry, we found that the majority of CAPs, including the force-sensing protein vinculin, interact with CCCs outside of AJs. Accordingly, structural modeling shows that there is not enough space for CAPs the size of vinculin to integrate into E clusters. Using two CAPs, scribble and erbin, as examples, we provide evidence that these proteins form separate clusters, which we term "C clusters." As proof of principle, we show, by using cadherin ectodomain monoclonal antibodies (mAbs), that mAb-bound E-cadherin forms separate clusters that undergo interactions. Taken together, our data suggest that, in addition to its role in cell-cell adhesion, CAP-driven CCC clustering serves to organize cytoplasmic proteins into distinct domains that may synchronize signaling networks of neighboring cells within tissues.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2105550118