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First published online September 19, 2007
doi: 10.1242/10.1242/jcs.013771

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Mechanistic insights from structural studies of -catenin and its binding partners

¹ Departments of Biological Structure
² Departments of Biochemistry, University of Washington, Seattle, WA 98195, USA

View larger version (27K): [in this window] [in a new window]   Fig. 1. Roles of -catenin in the cell. -catenin binds to E-cadherin and -catenin at adherens junctions. In the vicinity of these juctions, -catenin binds to actin as a homodimer. In the absence of Wnt signaling, -catenin joins the destruction complex (green), where it is phosphorylated by CK1 and GSK-3, which causes it to be ubiquitylated by the -TrCP ubiquitin ligase and subsequently degraded by the proteasome. In the presence of a Wnt signal, -catenin is not degraded and it moves to the nucleus, where it associates with DNA-binding members of the Tcf/LEF family and other associated transcription factors (not all of which are shown in the figure). This results in the activation of Wnt-target genes. Mutations in APC, axin or -catenin lead to stabilization of -catenin in the absence of a Wnt signal and consequent upregulation of Wnt-target genes.

View larger version (30K): [in this window] [in a new window]   Fig. 2. Interaction of -catenin and its partners. (A) A summary of the regions of -catenin that the partners described here bind to. Black bars indicate regions of -catenin bound by the different partners whereas red dots indicate the sites on -catenin that bind to the phosphorylated Ser/Thr residues of E-cadherin and the APC 20aa repeats. APC p-20aa represents the phosphorylated form of the APC 20aa-repeat region. The red stars indicate the sites on -catenin phosphorylated by CK1 and GSK-3 that create the binding site for -TrCP. (B) Structure of the -catenin armadillo repeat domain. The positions of the charged buttons (K312 and K435) are shown as circled Bs. The center of the groove of the armadillo repeat domain is shown as a dashed red line.

View larger version (33K): [in this window] [in a new window]   Fig. 3. -catenin complexes in cell adhesion. Crystal structures of the -catenin armadillo repeat domain (yellow) in complex with the E-cadherin cytoplasmic domain (red) and the dimerization and -catenin-binding domain of -catenin (green) were superimposed on the basis of shared -catenin residues 145-148. Note the disruption of the first helix in the armadillo repeat domain upon -catenin binding, which potentially produces a hinge, allowing structural flexibility between -catenin and -catenin. -catenin Y142, which disrupts -catenin binding upon phosphorylation, and Y654, which modulates the interaction between -catenin and E-cadherin upon phosphorylation, are shown in purple. Red dashes indicate flexible regions of E-cadherin.

View larger version (38K): [in this window] [in a new window]   Fig. 4. Structure of -catenin complexes in the -catenin destruction complex. Crystal structures of the -catenin armadillo repeat domain in complex with the phosphorylated third 20aa repeat of APC (in red) and the -catenin-binding domain of axin (in blue) were superimposed on the structure of the -catenin armadillo repeat domain. The positions of the four phosphorylated residues in APC 20aa repeat 3 are shown.

View larger version (59K): [in this window] [in a new window]   Fig. 5. Structure of a -catenin transcriptional complex. Crystal structure of the -catenin armadillo repeat domain in complex with Tcf4 (red) and BCL9 (cyan). The charged button lysines are shown in blue.

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