Sorting of cadherin–catenin-associated proteins into individual clusters

Regina B. Troyanovsky, Alina P. Sergeeva, Indrajyoti Indra, Chi Shuo Chen, Rei Kato, Lawrence Shapiro, Barry Honig*, Sergey M. Troyanovsky

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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 cis and trans 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 trans 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.

Original languageEnglish (US)
Article numbere2105550118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number29
DOIs
StatePublished - Jul 20 2021

Keywords

  • Cadherin | catenins | cadherin-associated proteins | adherens junctions | protein sorting

ASJC Scopus subject areas

  • General

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