Structural and functional characterization of the {alpha}-catenin{middle dot}{beta}-catenin binding interface in Caenorhabditis elegans reveals conserved requirements for cell-cell adhesion in metazoans [Protein Structure and Folding]

Stable tissue integrity during embryonic development relies on the function of the cadherin-catenin complex (CCC). The C. elegans CCC is a useful paradigm for analyzing in vivo requirements for specific interactions among the core components of the CCC, and provides a unique opportunity to examine evolutionarily conserved mechanisms that govern the interaction between α- and β-catenin. HMP-1, unlike its mammalian homolog α-catenin, is constitutively monomeric and its binding affinity for HMP-2/βcatenin is higher than that of α-catenin for β-catenin. A crystal structure shows that the HMP-1·HMP-2 complex forms a five-helical bundle structure distinct from the structure of the mammalian α-catenin·β-catenin complex. Deletion analysis based on the crystal structure shows that the first helix of HMP-1 is necessary for binding HMP-2 avidly in vitro and for efficient recruitment of HMP-1 to adherens junctions in embryos. HMP-2 S47 and Y69 flank its binding interface with HMP-1, and we show that phosphomimetic mutations at these two sites decrease binding affinity of HMP-1 to HMP-2 by 40-100 fold in vitro. In vivo rescue experiments using HMP-2 S47E and Y69E mutants showed that they are unable to rescue hmp-2(zu364) mutants, suggesting that phosphorylation of HMP-2 on S47 and Y69 could be important for regulating CCC formation in C. elegans. Our data provide novel insights into how cadherin-dependent cell-cell adhesion is modulated in metazoans by conserved elements as well as features unique to specific organisms.

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