ß-catenin plays essential role in cell adherens junctions - connecting cytoplasmic domains and actin cytoskeleton - and in the canonical Wnt pathway - related to embryonic development. Deregulation of this protein activity is associated with cancer and other human diseases, for example, the upregulation of its transcriptional activity is stimulated in most colon cancers. Therefore, ß-catenin is an important target for developing treatment for multiple diseases, with considerable interest in its structure.
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 helix C, 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.
The sequences of the protein terminal domains are less conserved than the armadillo repeat domain and mediate a subset of protein-protein interactions. It is observed that the helix C constitutes the C-terminal domain, and the N terminus of armadillo repeat has an alpha helix. Both N- and C-terminal domains do not interact with the armadillo repeat domain.
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.
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.
Signaling
In baseline conditions without Wnt signaling, ß-catenin concentrations are low in both the cytoplasm and the nucleus [1].
In the absence of Wnt, the destruction complex, formed by APC, Axin, CK1ɑ and GSK, is active and causes the degradation of ß-catenin through proteasome. [1]
Initially it is recognized by APC and Axin that promote the phosphorylation of Ser45 by CK1ɑ. This facilitates 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.[1]
Wnt signaling causes inhibition of the formation of the destruction complex, which leads to an increase in ß-catenin in the cytoplasm.
Even without nuclear localization signal (NLS) or nuclear export signal (NES) in its sequence, ß-catenin is translocated to the nucleus. Its transport is mainly due to direct interaction with nuclear pore complex (NPC), with Nup358 being the most important. The last three ARM repetitions R10, R11 and R12 are crucial for the import and export. The phosphorylation of Tyr654 increases the import and therefore the signaling. FoxM1 interacts with R11 and R12 repeats increasing importation into mammalian cells; alternatively or additionally, FoxM1 can decrease the export.
Most of the transcription factors that bind to beta-catenin depend on the interaction with the last ARM repeat and Helix-C being essential for its functioning; conversely, BCL9 binds to the first ARM repeat in the N-terminal region. Phosphorylations of Tyr654 and Ser675 make the C-terminal tail more accessible. Mutations that cause the amino acid Lys49 to change are found in several types of cancer. Lys345 acetylation is more frequent in colon cancer with Wnt / b-catenin hyperactivity.
Binding sites
