Crystal Structure of a β-Catenin/Tcf Complex

Graham, TC; Weaver, Carole; Mao, Feng; Kimelman, David; Xu, Wenqing

doi:10.1016/s0092-8674(00)00192-6

Cited by 384 publications

(397 citation statements)

References 45 publications

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“…The interaction of various Wnts (Wnt1, Wnt3a, and Wnt8) with their receptors (Fz) and co-receptors (LRP/5/6) triggers the recruitment of Axin to LRP6, promoting the dissociation of β-catenin from Axin and thereby inhibiting β-catenin phosphorylation and its subsequent degradation [33,34]. Biochemical and structural studies have demonstrated that Axin binds to β-catenin at a site on armadillo repeats 3-5 and that Phe253 and Lys292 of β-catenin contribute to this interaction [35][36][37]. In our study, just as in the case of Wnt-mediated Axin inactivation, SKL2001 inhibited both the CK1-and GSK-3β-mediated phosphorylation of β-catenin at Ser45 and Ser33/37/Thr41, respectively, in HEK293 cells.…”

Section: Discussionmentioning

confidence: 99%

Small molecule-based disruption of the Axin/β-catenin protein complex regulates mesenchymal stem cell differentiation

Gwak

Hwang

Park³

et al. 2011

Cell Res

113

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The Wnt/β-catenin pathway plays important roles in the differentiation of multiple cell types, including mesenchymal stem cells. Using a cell-based chemical screening assay with a synthetic chemical library of 270 000 compounds, we identified the compound SKL2001 as a novel agonist of the Wnt/β-catenin pathway and uncovered its molecular mechanism of action. SKL2001 upregulated β-catenin responsive transcription by increasing the intracellular β-catenin protein level and inhibited the phosphorylation of β-catenin at residues Ser33/37/Thr41 and Ser45, which would mark it for proteasomal degradation, without affecting CK1 and GSK-3β enzyme activities. Biochemical analysis revealed that SKL2001 disrupted the Axin/β-catenin interaction, which is a critical step for CK1-and GSK-3β-mediated phosphorylation of β-catenin at Ser33/37/Thr41 and Ser45. The treatment of mesenchymal stem cells with SKL2001 promoted osteoblastogenesis and suppressed adipocyte differentiation, both of which were accompanied by the activation of Wnt/β-catenin pathway. Our findings provide a new strategy to regulate mesenchymal stem cell differentiation by modulation of the Wnt/β-catenin pathway.

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Section: Discussionmentioning

confidence: 99%

Small molecule-based disruption of the Axin/β-catenin protein complex regulates mesenchymal stem cell differentiation

Gwak

Hwang

Park³

et al. 2011

Cell Res

113

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“…This structure forms a rigid scaffold for the binding of many factors, including the Tcf transcription factor, the cell adhesion protein cadherin, APC, Axin and others (Graham et al, 2000(Graham et al, , 2002Huber and Weis, 2001; Spink et al, 2001;Xing et al, 2003Xing et al, , 2004Ha et al, 2004;Liu et al, 2006). Surprisingly, many of these factors bind the same two lysine residues in repeats 5 and 8, which we have called the 'charged buttons' since they serve a major role in attaching partners to b-catenin via electrostatic interactions (Graham et al, 2000). The N-and C-terminal regions are much smaller, and appear to form mostly flexible regions that primarily interact with transcriptional activating factors.…”

Section: B-cateninmentioning

confidence: 99%

β-Catenin destruction complex: insights and questions from a structural perspective

2006

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At the heart of the canonical Wnt signaling pathway is the b-catenin destruction complex, which functions in the absence of Wnt signaling to keep the cytosolic and nuclear levels of b-catenin very low by promoting the phosphorylation and ubiquitination of b-catenin. Structural studies, combined with other experimental approaches, have begun to provide important insights into the mechanism of the destruction complex. We suggest a working model for the destruction complex based on the existing structural and experimental data, and focus on the questions that this model and other studies have raised about the function of the complex in both the normal and Wnt-inhibited states.

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“…Residues that are conserved among other bilaterians but have changed in vertebrate betacatenin or plakoglobin are red. Note that: (1) one change has occurred in this particular region of vertebrate beta-catenin (arrowhead); and that (2) hot spots for interaction with cadherin, Axin, APC, and TCF factors have been identified at these repeats, especially the acidic groove, in mouse/human beta-catenin (Graham et al, 2000;von Kries et al, 2000;Huber and Weis, 2001). Strong, stabilizing selection is most likely imposed by essential intra-and intermolecular interactions that account for the structural and functional properties of beta-catenin.…”

Section: Structural Context Of Conserved Residuesmentioning

confidence: 99%

“…These residues are conserved in Ce Hmp-2 and all bilaterian beta-catenins but have changed in both Ce Bar-1 and Ce Wrm-1. However, structural analyses of TCF/beta-catenin and cadherin/ beta-catenin complexes indicate that beta-catenin utilizes some of the same residues in R5-R8 to interact with both TCF and cadherins (Graham et al, 2000;Huber and Weis, 2001). Therefore, signaling and adhesion constraints may be superimposed on some of the same residues, explaining their conservation in both Ce Hmp-2 and Ce Bar-1.…”

Section: Loss Of Constraints In C Elegans Beta-cateninsmentioning

confidence: 99%

“…At least two interactions of stabilized betacatenin are required for its function in transcriptional activation. Beta-catenin binds to TCF/LEF-1 proteins via R3-R10 (Graham et al, 2000;von Kries et al, 2000). The beta-catenin/TCF complex can bind via a TCF binding domain to sites in the regulatory regions of wnt-target genes (Huber et al,'96;van de Wetering et al,'97).…”

mentioning

confidence: 99%

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Protein evolution: structure‐function relationships of the oncogene beta‐catenin in the evolution of multicellular animals

2003

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Beta-catenin functions as a cytoskeletal linker protein in cadherin-mediated adhesion and as a signal mediator in wnt-signal transduction pathways. We use a novel integrative approach, combining evolutionary, genomic, and three-dimensional structural data to analyze and trace the structural and functional evolution of beta-catenin genes. This approach also enabled us to examine the effects of gene duplication on the structure and function of beta-catenin genes in Drosophila, C. elegans, and vertebrates. By sampling a large number of different taxa, we identified both ancestral and derived motifs and residues within the different regions of the beta-catenin proteins. Projecting amino acid substitutions onto the three-dimensional structure established for mouse beta-catenin, we identified specific domains that exhibit loss and gain of selective constraints during beta catenin evolution. Structural changes, changes in the amino acid substitution rate, and the appearance of novel functional domains in beta-catenin can be mapped to specific branches on the metazoan tree. Together, our analyses suggest that a single, beta-catenin gene fulfilled both adhesion and signaling functions in the last common ancestor of metazoans some 700 million years ago. In addition, gene duplications facilitated the evolution of beta-catenins with novel functions and allowed the evolution of multiple, single-function proteins (cell adhesion or wnt-signaling) from the ancestral, dual-function protein. Integrative methods such as those we have applied here, utilizing the 'natural experiments' present in animal diversity, can be employed to identify novel and shared functional motifs and residues in virtually any protein among the proteomes of model systems and humans.

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Crystal Structure of a β-Catenin/Tcf Complex

Cited by 384 publications

References 45 publications

Small molecule-based disruption of the Axin/β-catenin protein complex regulates mesenchymal stem cell differentiation

Small molecule-based disruption of the Axin/β-catenin protein complex regulates mesenchymal stem cell differentiation

β-Catenin destruction complex: insights and questions from a structural perspective

Protein evolution: structure‐function relationships of the oncogene beta‐catenin in the evolution of multicellular animals

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