Structure

The zebrafish ß-catenin is constituted by 781 amino acids and contains a core of 12 armadillo repeats domain and an alpha helix, the , at the beginning of the ß-catenin C-terminal domain. The armadillo domain is made of three helices in each repeat and has a particular site which is positively charged, constituting the binding surface for the majority of ß-catenin ligands. ^[1]

are less conserved than the armadillo repeat domain and mediate a subset of protein-protein interactions. It is observed that the , and the . Both do not interact with the armadillo repeat domain. ^[1]

In contrast to the armadillo ligand-binding structural groove, the C-terminal tail is highly negatively charged. It caps the hydrophobic surface formed by the C-terminal end of the armadillo repeats. Thereby, this structure forms part of the superhelical structure core of ß-catenin together with armadillo repeat domain. ^[1]

It is possible that the helix-C is important for the transactivation of Wnt-responsive genes, but not for the cell adhesion through cadherins. Hence, this same β-catenin region is also the binding site of transcriptional inhibitors that compete directly with TCF for β-catenin binding.^[1]

Cell Adhesion

In the absence of Wnt stimulus, the ß-catenin is located at the cytoplasmic side of the membrane as a component of cadherin-based cell-cell connections. Cadherins are transmembrane glycoproteins calcium-dependent adhesion that can link to ß-catenin through their cytoplasmic tails. The cadherin-catenin complex forms adherens junctions that polarize epithelial tissues and hold the cells together. ^[2]

The most known interaction occurs between ß-catenin and E-cadherin (epithelial cadherin). They are associated while still in the endoplasmic reticulum and interfering with the binding of these proteins results in proteasomal degradation of the cadherin. First, ⲁ-catenin binds to ß-catenin at the , resulting in an ⲁ-catenin/ß-catenin heterodimer. This binding stabilizes ß-catenin in the hinged form, and E-cadherin can connect simultaneously. The interaction surface is extensive, covering the entire length of the ß-catenin ARM repeat domain and involving the C-terminal 100 residues of the cadherin cytoplasmic domain. ^{[3] [4]}

The ß-catenin destruction complex

In baseline conditions without Wnt signaling, ß-catenin concentrations are low in both the cytoplasm and the nucleus. Then, the destruction complex, formed by APC, Axin, CK1ɑ and GSK, is active and causes the degradation of the protein through proteasome. Initially it is recognized by APC and Axin that promote the phosphorylation of Ser45 by CK1ɑ. This facilitates the phosphorylation by GSK in the residues of the amino acids Thr41, Ser37 and Ser33. The last two, when phosphorylated, leads to recognition by ß-TrCP and consequently ubiquitination by an E3 ligase and degradation by 26S proteasome. ^[3]

DNA binding and transcription

The inhibition of ß-catenin destruction leads to increased levels of the protein in cytoplasm and its translocation into the nucleus. ß-catenin interacts with different nuclear pore complex components and ARM repeats are crucial for its import and export. FoxM1 also facilitates its nuclear translocation directly interacting with ARM repeats . FoxM1 forms a complex with ß-catenin/TCF on the promoters of Wnt target genes. Once in the nucleus, ß-catenin and its DNA binding partners can activate transcription of Wnt/ß-catenin target genes. Therefore, ß-catenin can only initiates transcription in a multimeric complex, as its central transcriptional activator. ^[3]

TCF transcription factors serve as the main nuclear member of ß-catenin multimeric complex. TCFs bind to DNA enhancers and ß-catenin acts as a link in a chain between them and others transcriptional coactivators. This interaction can be modulated to enhance, repress os switch off ß-catenin-mediated transcription. The majority of these transcription coactivators binds to the and many of them can affect chromatin structure. Indeed, it seems that the C-terminus region of ß-catenin coordinates the recruitment and sequential exchange of these proteins. Binding of ß-catenin to TCF is blocked by some proteins such as ICAT, which interacts with the central ARM repeat of ß-catenin. ^[3]

References

1. ↑ ^{1.0 1.1 1.2 1.3 1.4} Xing Y, Takemaru K, Liu J, Berndt JD, Zheng JJ, Moon RT, Xu W. Crystal structure of a full-length beta-catenin. Structure. 2008 Mar;16(3):478-87. PMID:18334222 doi:10.1016/j.str.2007.12.021
2. ↑ Developmental Biology . Eleventh Edition. By Scott F. Gilbert and Michael J. F. Barresi. Sunderland (Massachusetts): Sinauer Associates. ISBN: 978-1-60535-470-5. 2016.
3. ↑ ^{3.0 3.1 3.2 3.3} Valenta T, Hausmann G, Basler K. The many faces and functions of beta-catenin. EMBO J. 2012 Jun 13;31(12):2714-36. doi: 10.1038/emboj.2012.150. Epub 2012 May, 22. PMID:22617422 doi:http://dx.doi.org/10.1038/emboj.2012.150
4. ↑ Huber, A. H., & Weis, W. I. (2001). The structure of the β-catenin/E-cadherin complex and the molecular basis of diverse ligand recognition by β-catenin. Cell, 105(3), 391-402.