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Structure of beta-catenin with Lef-1
Structural highlights
FunctionCTNB1_MOUSE Key downstream component of the canonical Wnt signaling pathway. In the absence of Wnt, forms a complex with AXIN1, AXIN2, APC, CSNK1A1 and GSK3B that promotes phosphorylation on N-terminal Ser and Thr residues and ubiquitination of CTNNB1 via BTRC and its subsequent degradation by the proteasome. In the presence of Wnt ligand, CTNNB1 is not ubiquitinated and accumulates in the nucleus, where it acts as a coactivator for transcription factors of the TCF/LEF family, leading to activate Wnt responsive genes. Involved in the regulation of cell adhesion. Acts as a negative regulator of centrosome cohesion. Involved in the CDK2/PTPN6/CTNNB1/CEACAM1 pathway of insulin internalization. Blocks anoikis of malignant kidney and intestinal epithelial cells and promotes their anchorage-independent growth by down-regulating DAPK2 (By similarity). Publication Abstract from PubMedIn the Wnt/beta-catenin signaling pathway, beta-catenin activates target genes through its interactions with the T-cell factor/lymphoid enhancer-binding factor (TCF/Lef) family of transcription factors. The crystal structures of complexes between the beta-catenin armadillo domain and the Lef-1 N-terminal domain show that the overall conformation and many of the interactions are similar to other published structures of TCFs bound to beta-catenin. However, a second salt bridge in other TCF-beta-catenin structures is absent in the structure of beta-catenin-Lef-1 complex, indicating that this feature is not obligatory for beta-catenin binding. Casein kinase II (CK2) has been shown to act as a positive regulator of Wnt signaling, and Lef-1 is a substrate of CK2. In vitro phosphorylation of purified Lef-1 was used to examine the effect of CK2 on the interaction of Lef-1 with beta-catenin. Mass spectrometry data show that CK2 phosphorylation of Lef-1 N-terminal domain results in a single phosphorylation site at Ser40. Isothermal titration calorimetry revealed that beta-catenin binds to nonphosphorylated or CK2-phosphorylated Lef-1 with the same affinity, which is consistent with the absence of phospho-Ser40 interactions in the crystal structure of phosphorylated Lef-1 N-terminal domain bound to beta-catenin. These data indicate that the effect of CK2 on the Wnt/beta-catenin pathway does not appear to be at the level of the Lef-1-beta-catenin interaction. Biochemical and structural characterization of beta-catenin interactions with nonphosphorylated and CK2-phosphorylated Lef-1.,Sun J, Weis WI J Mol Biol. 2011 Jan 14;405(2):519-30. doi: 10.1016/j.jmb.2010.11.010. Epub 2010 , Nov 12. PMID:21075118[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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