Crystal Structure of a Full-Length β-Catenin

Xing, Yi; Takemaru, Ken Ichi; Liu, Jing; Berndt, Jason D.; Zheng, Jie; Moon, Randall T.; Xu, Wenqing

doi:10.1016/j.str.2007.12.021

Cited by 167 publications

(172 citation statements)

References 53 publications

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“…It has been previously speculated that low affinity charge interactions between the basic arm repeat domain and acidic terminal regions may effectively shield the arm repeats from nonspecific interactions (29). Consistent with this model, ␤-catenin lacking its entire CTD was found to coimmunoprecipitate numerous 32 P radioactively labeled species (supplemental Fig.…”

Section: Discussionsupporting

confidence: 65%

“…With similar methods, two studies found that the CTD of ␤-catenin could compete its binding to the cadherin (39,47), but not TCF (47), raising the possibility that in a full-length protein the CTD may fold back along the arm domain in a closed conformation that restricts binding to some partners (27,47). However, specific binding between the CTD and the arm domain was not supported when Coomassie-stained gels were employed to quantify binding (19) or NMR spectroscopy was used to detect transient weak interactions (29). As these experi- ments are done in trans, it has remained untested whether a CTD tethered in cis could interact more effectively.…”

Section: Discussionmentioning

confidence: 99%

“…Recent evidence indicates that the CTD negatively impacts ␤-catenin binding to axin and APC using the isothermal titration calorimetry method (19), but how the CTD restricts ␤-catenin binding to axin has remained unresolved. Although the CTD plays an established role in recruiting factors required for gene expression, most interaction partners depend on the more proximal, structured elements of this region, such as helix C, which directly follows the 12th arm repeat (28,29). Functions for the more distal, unstructured region of the CTD remain poorly defined despite its contribution to ␤-catenin nuclear signaling (27).…”

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confidence: 99%

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The Terminal Region of β-Catenin Promotes Stability by Shielding the Armadillo Repeats from the Axin-scaffold Destruction Complex

Chew

Maher

et al. 2009

Journal of Biological Chemistry

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Post-translational stabilization of ␤-catenin is a key step in Wnt signaling, but the features of ␤-catenin required for stabilization are incompletely understood. We show that forms of ␤-catenin lacking the unstructured C-terminal domain (CTD) show faster turnover than full-length or minimally truncated ␤-catenins. Mutants that exhibit faster turnover show enhanced association with axin in co-transfected cells, and excess CTD polypeptide can compete binding of the ␤-catenin armadillo (arm) repeat domain to axin in vitro, indicating that the CTD may restrict ␤-catenin binding to the axin-scaffold complex. Fluorescent resonance energy transmission (FRET) analysis of cyan fluorescent protein (CFP)-arm-CTD-yellow fluorescent protein ␤-catenin reveals that the CTD of ␤-catenin can become spatially close to the N-terminal arm repeat region of ␤-catenin. FRET activity is strongly diminished by the coexpression of ␤-catenin binding partners, indicating that an unliganded groove is absolutely required for an orientation that allows FRET. Amino acids 733-759 are critical for ␤-catenin FRET activity and stability. These data indicate that an N-terminal orientation of the CTD is required for ␤-catenin stabilization and suggest a model where the CTD extends toward the N-terminal arm repeats, shielding these repeats from the ␤-catenin destruction complex.The protein ␤-catenin serves two fundamental roles in the formation and maintenance of tissues. At the cell surface, ␤-catenin binds the cytoplasmic domain of cadherin-type adhesion receptors, allowing cells to engage their neighbors through robust intercellular adhering junctions. In the cytoplasm and nucleus, a cadherin-independent pool of ␤-catenin interacts with TCF 3 -type transcription factors to activate genes that produce cells with distinct identities. The abundance of this cytosolic/nuclear pool of ␤-catenin is largely determined by the presence of extracellular Wnt factors, which initiate a signaling cascade that prevents the continual destruction of cadherin-free ␤-catenin.The destruction of ␤-catenin is carried out by a highly coordinated series of phosphorylation events. In the absence of Wnt, the N terminus of ␤-catenin is sequentially phosphorylated by casein kinase 1␣ and glycogen synthase kinase 3␤ (GSK3␤) (1, 2). Phosphorylation of ␤-catenin by GSK at residues serine 33 and 37 allows recognition by the E3-ligase component ␤TrCP, which when part of the SCF ␤TrCP complex, catalyzes the ubiquitylation and rapid degradation of ␤-catenin (3). This phosphorylation-dependent degradation of ␤-catenin depends on the scaffold protein, axin, and the tumor suppressor APC. Axin has binding sites for casein kinase 1␣, GSK3␤, ␤-catenin, and APC, so that phosphorylation of axin by casein kinase 1␣ and GSK3␤ increases binding to ␤-catenin (4 -6), allowing the N-terminal region of ␤-catenin to be a more efficient substrate of casein kinase 1␣ and GSK3␤ (7). Axin also promotes phosphorylation of APC by casein kinase 1⑀ and GSK3␤ (8,9), increasing the affinity of APC for ␤-ca...

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Section: Discussionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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The Terminal Region of β-Catenin Promotes Stability by Shielding the Armadillo Repeats from the Axin-scaffold Destruction Complex

Chew

Maher

et al. 2009

Journal of Biological Chemistry

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“…HQ234356) has diagnostic protein domains and residues indicative of the ability to interact with classical cadherins. Oc_bcat contains at least 11 of the 12 conserved armadillo (arm) repeats (36,37) that are typical of eumetazoan β-catenin proteins (Fig. 3C) and shows 66.4% amino acid sequence identity with human β-catenin over the conserved arm-repeat region.…”

Section: Resultsmentioning

confidence: 99%

Origin of metazoan cadherin diversity and the antiquity of the classical cadherin/β-catenin complex

Nichols

Roberts

Richter

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

170

196

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The evolution of cadherins, which are essential for metazoan multicellularity and restricted to metazoans and their closest relatives, has special relevance for understanding metazoan origins. To reconstruct the ancestry and evolution of cadherin gene families, we analyzed the genomes of the choanoflagellate Salpingoeca rosetta, the unicellular outgroup of choanoflagellates and metazoans Capsaspora owczarzaki, and a draft genome assembly from the homoscleromorph sponge Oscarella carmela. Our finding of a cadherin gene in C. owczarzaki reveals that cadherins predate the divergence of the C. owczarzaki, choanoflagellate, and metazoan lineages. Data from these analyses also suggest that the last common ancestor of metazoans and choanoflagellates contained representatives of at least three cadherin families, lefftyrin, coherin, and hedgling. Additionally, we find that an O. carmela classical cadherin has predicted structural features that, in bilaterian classical cadherins, facilitate binding to the cytoplasmic protein β-catenin and, thereby, promote cadherin-mediated cell adhesion. In contrast with premetazoan cadherin families (i.e., those conserved between choanoflagellates and metazoans), the later appearance of classical cadherins coincides with metazoan origins.

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“…5 Structurally, b-catenin contains a series of 12 armadillo repeats, each of which is approximately 40 amino acids, surrounded by unstructured N-and C-terminal domains. 6 Protein-protein interaction mapping experiments have demonstrated that all 3 b-catenin domains are involved in both signaling and cytoskeletal interaction. 7,8 Over 38 b-catenin interaction partners have been documented (http://www.stanford.edu/group/nusselab/cgi-bin/ wnt/protein_interactions).…”

Section: Introductionmentioning

confidence: 99%

Functional inhibition of β-catenin-mediatedWnt signaling by intracellular VHHantibodies

Newnham¹,

Wright²,

Holdsworth³

et al. 2015

mAbs

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(2015) Functional inhibition of β-catenin-mediatedWnt signaling by intracellular VHHantibodies, mAbs, 7:1, 180-191, DOI: 10.4161/19420862.2015.989023 To link to this article: https://doi.org/10. 4161/19420862.2015 The Wnt signaling pathway is of central importance in embryogenesis, development and adult tissue homeostasis, and dysregulation of this pathway is associated with cancer and other diseases. Despite the developmental and potential therapeutic significance of this pathway, many aspects of Wnt signaling, including the control of the master transcriptional co-activator b-catenin, remain poorly understood. In order to explore this aspect, a diverse immune llama VHH phagemid library was constructed and panned against b-catenin. VHH antibody fragments from the library were expressed intracellularly, and a number of antibodies were shown to possess function-modifying intracellular activity in a luciferase-based Wnt signaling HEK293 reporter bioassay. Further characterization of one such VHH (named LL3) confirmed that it bound endogenous b-catenin, and that it inhibited the Wnt signaling pathway downstream of the destruction complex, while production of a control Ala-substituted complementarity-determining region (CDR)3 mutant demonstrated that the inhibition of b-catenin activity by the parent intracellular antibody was dependent on the specific CDR sequence of the antibody.

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Crystal Structure of a Full-Length β-Catenin

Cited by 167 publications

References 53 publications

The Terminal Region of β-Catenin Promotes Stability by Shielding the Armadillo Repeats from the Axin-scaffold Destruction Complex

The Terminal Region of β-Catenin Promotes Stability by Shielding the Armadillo Repeats from the Axin-scaffold Destruction Complex

Origin of metazoan cadherin diversity and the antiquity of the classical cadherin/β-catenin complex

Functional inhibition of β-catenin-mediatedWnt signaling by intracellular VHHantibodies

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