Beta-catenin

1G3J, 1JDH, 1JPW, 1LUJ, 1P22, 1QZ7, 1T08, 1TH1, 2GL7, 2Z6H, 3DIW, 3SL9, 3SLA, 3TX7, 4DJS, 3FQN, 3FQR149912387ENSG00000168036ENSMUSG00000006932P35222Q02248NM_001098209NM_001098210NM_001904NM_001330729NM_001165902NM_007614NP_001091679NP_001091680NP_001317658NP_001895NP_001159374NP_031640Catenin beta-1, also known as β-catenin, is a protein that in humans is encoded by the CTNNB1 gene.1dow: CRYSTAL STRUCTURE OF A CHIMERA OF BETA-CATENIN AND ALPHA-CATENIN1g3j: CRYSTAL STRUCTURE OF THE XTCF3-CBD/BETA-CATENIN ARMADILLO REPEAT COMPLEX1i7w: BETA-CATENIN/PHOSPHORYLATED E-CADHERIN COMPLEX1i7x: BETA-CATENIN/E-CADHERIN COMPLEX1jdh: CRYSTAL STRUCTURE OF BETA-CATENIN AND HTCF-41jpp: The Structure of a beta-Catenin Binding Repeat from Adenomatous Polyposis Coli (APC) in Complex with beta-Catenin1jpw: Crystal Structure of a Human Tcf-4 / beta-Catenin Complex1luj: Crystal Structure of the Beta-catenin/ICAT Complex1m1e: Beta-catenin armadillo repeat domain bound to ICAT1qz7: Beta-catenin binding domain of Axin in complex with beta-catenin1t08: Crystal structure of beta-catenin/ICAT helical domain/unphosphorylated APC R31th1: Beta-catenin in complex with a phosphorylated APC 20aa repeat fragment1v18: THE CRYSTAL STRUCTURE OF BETA-CATENIN ARMADILLO REPEAT COMPLEXED WITH A PHOSPHORYLATED APC 20MER REPEAT.2bct: THE ARMADILLO REPEAT REGION FROM MURINE BETA-CATENIN2gl7: Crystal Structure of a beta-catenin/BCL9/Tcf4 complex3bct: THE ARMADILLO REPEAT REGION FROM MURINE BETA-CATENIN Catenin beta-1, also known as β-catenin, is a protein that in humans is encoded by the CTNNB1 gene. β-catenin is a dual function protein, involved in regulation and coordination of cell–cell adhesion and gene transcription. In humans, the CTNNB1 protein is encoded by the CTNNB1 gene. In Drosophila, the homologous protein is called armadillo. β-catenin is a subunit of the cadherin protein complex and acts as an intracellular signal transducer in the Wnt signaling pathway. It is a member of the catenin protein family and homologous to γ-catenin, also known as plakoglobin. Beta-catenin is widely expressed in many tissues. In cardiac muscle, beta-catenin localizes to adherens junctions in intercalated disc structures, which are critical for electrical and mechanical coupling between adjacent cardiomyocytes. Mutations and overexpression of β-catenin are associated with many cancers, including hepatocellular carcinoma, colorectal carcinoma, lung cancer, malignant breast tumors, ovarian and endometrial cancer. Alterations in the localization and expression levels of beta-catenin have been associated with various forms of heart disease, including dilated cardiomyopathy. β-catenin is regulated and destroyed by the beta-catenin destruction complex, and in particular by the adenomatous polyposis coli (APC) protein, encoded by the tumour-suppressing APC gene. Therefore, genetic mutation of the APC gene is also strongly linked to cancers, and in particular colorectal cancer resulting from familial adenomatous polyposis (FAP). Beta-catenin was initially discovered in the early 1990s as a component of a mammalian cell adhesion complex: a protein responsible for cytoplasmatic anchoring of cadherins. But very soon, it was realized that the Drosophila protein armadillo – implicated in mediating the morphogenic effects of Wingless/Wnt – is homologous to the mammalian β-catenin, not just in structure but also in function. Thus beta-catenin became one of the very first examples of moonlighting: a protein performing more than one radically different cellular function. The core of beta-catenin consists of several very characteristic repeats, each approximately 40 amino acids long. Termed armadillo repeats, all these elements fold together into a single, rigid protein domain with an elongated shape – called armadillo (ARM) domain. An average armadillo repeat is composed of three alpha helices. The first repeat of β-catenin (near the N-terminus) is slightly different from the others – as it has an elongated helix with a kink, formed by the fusion of helices 1 and 2. Due to the complex shape of individual repeats, the whole ARM domain is not a straight rod: it possesses a slight curvature, so that an outer (convex) and an inner (concave) surface is formed. This inner surface serves as a ligand-binding site for the various interaction partners of the ARM domains. The segments N-terminal and far C-terminal to the ARM domain do not adopt any structure in solution by themselves. Yet these intrinsically disordered regions play a crucial role in beta-catenin function. The N-terminal disordered region contains a conserved short linear motif responsible for binding of TrCP1 (also known as β-TrCP) E3 ubiquitin ligase – but only when it is phosphorylated. Degradation of β-catenin is thus mediated by this N-terminal segment. The C-terminal region, on the other hand, is a strong transactivator when recruited onto DNA. This segment is not fully disordered: part of the C-terminal extension forms a stable helix that packs against the ARM domain, but may also engage separate binding partners. This small structural element (HelixC) caps the C-terminal end of the ARM domain, shielding its hydrophobic residues. HelixC is not necessary for beta-catenin to function in cell-cell adhesion. On the other hand, it is required for Wnt signaling: possibly to recruit various coactivators, such as 14-3-3zeta. Yet its exact partners among the general transcription complexes are still unknown. Notably, the C-terminal segment of β-catenin can mimic the effects of the entire Wnt pathway if artificially fused to the DNA binding domain of LEF1 transcription factor. Plakoglobin (also called gamma-catenin) has a strikingly similar architecture to that of beta-catenin. Not only their ARM domains resemble each other in both architecture and ligand binding capacity, but the N-terminal β-TrCP-binding motif is also conserved in plakoglobin, implying common ancestry and shared regulation with β-catenin. However, plakoglobin is a very weak transactivator when bound to DNA – this is probably caused by the divergence of their C-terminal sequences (plakoglobin appears to lack the transactivator motifs, and thus inhibits the Wnt pathway target genes instead of activating them). As sketched above, the ARM domain of beta-catenin acts as a platform to which specific linear motifs may bind. Located in structurally diverse partners, the β-catenin binding motifs are typically disordered on their own, and typically adopt a rigid structure upon ARM domain engagement – as seen for short linear motifs. However, β-catenin interacting motifs also have a number of peculiar characteristics. First, they might reach or even surpass the length of 30 amino acids in length, and contact the ARM domain on an excessively large surface area. Another unusual feature of these motifs is their frequently high degree of phosphorylation. Such Ser/Thr phosphorylation events greatly enhance the binding of many β-catenin associating motifs to the ARM domain. The structure of beta-catenin in complex with the catenin binding domain of the transcriptional transactivation partner TCF provided the initial structural roadmap of how many binding partners of beta-catenin may form interactions. This structure demonstrated how the otherwise disordered N-terminus of TCF adapted what appeared to be a rigid conformation, with the binding motif spanning many beta-catenin repeats. Relatively strong charged interaction 'hot spots' were defined (predicted, and later verified, to be conserved for the beta-catenin/E-cadherin interaction), as well as hydrophobic regions deemed important in the overall mode of binding and as potential therapeutic small molecule inhibitor targets against certain cancer forms. Furthermore, following studies demonstrated another peculiar characteristic, plasticity in the binding of the TCF N-terminus to beta-catenin.