PDBsum entry 1t08

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protein Protein-protein interface(s) links
Cell adhesion/cell cycle PDB id
Jmol PyMol
Protein chains
510 a.a. *
46 a.a. *
15 a.a. *
Waters ×327
* Residue conservation analysis
PDB id:
Name: Cell adhesion/cell cycle
Title: Crystal structure of beta-catenin/icat helical domain/unphosphorylated apc r3
Structure: Beta-catenin. Chain: a. Fragment: armadillo repeat (residues 146-664). Synonym: cadherin-associated protein. Pro2286. Engineered: yes. Beta-catenin-interacting protein 1. Chain: b. Fragment: helical domain (residues 8-53). Synonym: beta-catenin-interacting protein icat. Inhibitor
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: ctnnb1,ctnnb. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693. Gene: ctnnbip1,icat. Gene: apc,dp2.5.
Biol. unit: Trimer (from PQS)
2.10Å     R-factor:   0.204     R-free:   0.241
Authors: N.-C.Ha,T.Tonozuka,J.L.Stamos,W.I.Weis
Key ref:
N.C.Ha et al. (2004). Mechanism of phosphorylation-dependent binding of APC to beta-catenin and its role in beta-catenin degradation. Mol Cell, 15, 511-521. PubMed id: 15327768 DOI: 10.1016/j.molcel.2004.08.010
07-Apr-04     Release date:   12-Oct-04    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P35222  (CTNB1_HUMAN) -  Catenin beta-1
781 a.a.
510 a.a.
Protein chain
Pfam   ArchSchema ?
Q9NSA3  (CNBP1_HUMAN) -  Beta-catenin-interacting protein 1
81 a.a.
46 a.a.
Protein chain
Pfam   ArchSchema ?
P25054  (APC_HUMAN) -  Adenomatous polyposis coli protein
2843 a.a.
15 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     adherens junction assembly   1 term 
  Biochemical function     signal transducer activity     2 terms  


DOI no: 10.1016/j.molcel.2004.08.010 Mol Cell 15:511-521 (2004)
PubMed id: 15327768  
Mechanism of phosphorylation-dependent binding of APC to beta-catenin and its role in beta-catenin degradation.
N.C.Ha, T.Tonozuka, J.L.Stamos, H.J.Choi, W.I.Weis.
The transcriptional coactivator beta-catenin mediates Wnt growth factor signaling. In the absence of a Wnt signal, casein kinase 1 (CK1) and glycogen synthase kinase-3beta (GSK-3beta) phosphorylate cytosolic beta-catenin, thereby flagging it for recognition and destruction by the ubiquitin/proteosome machinery. Phosphorylation occurs in a multiprotein complex that includes the kinases, beta-catenin, axin, and the Adenomatous Polyposis Coli (APC) protein. The role of APC in this process is poorly understood. CK1epsilon and GSK-3beta phosphorylate APC, which increases its affinity for beta-catenin. Crystal structures of phosphorylated and nonphosphorylated APC bound to beta-catenin reveal a phosphorylation-dependent binding motif generated by mutual priming of CK1 and GSK-3beta substrate sequences. Axin is shown to act as a scaffold for substrate phosphorylation by these kinases. Phosphorylated APC and axin bind to the same surface of, and compete directly for, beta-catenin. The structural and biochemical data suggest a novel model for how APC functions in beta-catenin degradation.
  Selected figure(s)  
Figure 1.
Figure 1. Primary Structure of Axin and APC(A) Axin. The binding sites of partner proteins are indicated. RGS, regulator of G protein signaling-homologous domain; DIX, dishevelled and axin-interaction domain.(B) APC. The four β-catenin binding 15-mer repeats are shown as white boxes and labeled A–D, and the seven 20-mer repeats (labeled 1–7) are shown as black boxes. The three axin binding SAMP repeats are shown in gray. Olig, dimerization domain; arm, armadillo repeat domain; basic, basic region; dlg, Discs-large binding site.(C) Structure-based alignment of the human APC β-catenin binding sequences. Residue numbers are indicated. The standard alignments of the APC repeats are highlighted in yellow to show the shift in register revealed by the R3 complex structure. The “core homology region” is the basis of the standard alignments. The shaded region of R3 is observed in the nonphosphorylated structure. The five residues that constitute the motif for interaction with β-catenin arm repeats 5-9 are shown in red. The order of CK1 and GSK-3β phosphorylation is indicated on the alignment. The four serine residues visible in the structure are indicated in blue, and the two others that represent the priming phosphorylations are shown in green. The structure-based alignment of the E-cadherin sequence is indicated, including the locations of the three pSer residues (green boxes) observed in the crystal structure of its complex with β-catenin (Huber and Weis, 2001). The R6 sequence used in initial experiments is underlined.
Figure 2.
Figure 2. Structure of Unphosphorylated APC R3 Bound to β-Catenin(A) Ribbon diagram of the complex, with cylinders representing α helices. The β-catenin arm repeat domain is shown in gray (helices 1 and 2 of the arm repeat motif) and cyan (helix 3, which forms the groove) (Huber et al., 1997). The ICAT helical domain used for crystallization is shown in white. The superimposed crystal structures of the bound XTcf-3 (green), E-cadherin (yellow), APC-RA (blue), and APC-R3 (orange) ligands are shown.(B) Overlay of the extended peptide of R3 (orange) and E-cadherin (yellow) bound to β-catenin. Nitrogen and oxygen atoms are shown in blue and red, respectively. Residue numbers for cadherin are shown in parentheses.(C) Diagram of the interactions formed between APC R3 and β-catenin. APC residues are shown in ovals with key side chain interactions indicated. Hydrogen bonds and salt bridges are indicated by dashed lines, and nonpolar contacts by arcs.
  The above figures are reprinted by permission from Cell Press: Mol Cell (2004, 15, 511-521) copyright 2004.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20658693 A.Li, Y.Xing, B.Chan, N.Heisterkamp, J.Groffen, Z.Borok, P.Minoo, and C.Li (2010).
Cell type-specific expression of adenomatous polyposis coli in lung development, injury, and repair.
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20041275 A.Venerando, O.Marin, G.Cozza, V.H.Bustos, S.Sarno, and L.A.Pinna (2010).
Isoform specific phosphorylation of p53 by protein kinase CK1.
  Cell Mol Life Sci, 67, 1105-1118.  
21145761 C.Q.Lei, B.Zhong, Y.Zhang, J.Zhang, S.Wang, and H.B.Shu (2010).
Glycogen synthase kinase 3β regulates IRF3 transcription factor-mediated antiviral response via activation of the kinase TBK1.
  Immunity, 33, 878-889.  
19884009 D.Wu, and W.Pan (2010).
GSK3: a multifaceted kinase in Wnt signaling.
  Trends Biochem Sci, 35, 161-168.  
19966865 E.M.Kohler, K.Brauburger, J.Behrens, and J.Schneikert (2010).
Contribution of the 15 amino acid repeats of truncated APC to beta-catenin degradation and selection of APC mutations in colorectal tumours from FAP patients.
  Oncogene, 29, 1663-1671.  
  20182623 J.Heuberger, and W.Birchmeier (2010).
Interplay of cadherin-mediated cell adhesion and canonical Wnt signaling.
  Cold Spring Harb Perspect Biol, 2, a002915.  
20883218 M.Adamska, C.Larroux, M.Adamski, K.Green, E.Lovas, D.Koop, G.S.Richards, C.Zwafink, and B.M.Degnan (2010).
Structure and expression of conserved Wnt pathway components in the demosponge Amphimedon queenslandica.
  Evol Dev, 12, 494-518.  
20531295 S.H.Lee, G.N.Shen, Y.S.Jung, S.J.Lee, J.Y.Chung, H.S.Kim, Y.Xu, Y.Choi, J.W.Lee, N.C.Ha, G.Y.Song, and B.J.Park (2010).
Antitumor effect of novel small chemical inhibitors of Snail-p53 binding in K-Ras-mutated cancer cells.
  Oncogene, 29, 4576-4587.  
20305697 Y.Xu, S.H.Lee, H.S.Kim, N.H.Kim, S.Piao, S.H.Park, Y.S.Jung, J.I.Yook, B.J.Park, and N.C.Ha (2010).
Role of CK1 in GSK3beta-mediated phosphorylation and degradation of snail.
  Oncogene, 29, 3124-3133.  
19394332 A.Herbst, G.T.Bommer, L.Kriegl, A.Jung, A.Behrens, E.Csanadi, M.Gerhard, C.Bolz, R.Riesenberg, W.Zimmermann, W.Dietmaier, I.Wolf, T.Brabletz, B.Göke, and F.T.Kolligs (2009).
ITF-2 is disrupted via allelic loss of chromosome 18q21, and ITF-2B expression is lost at the adenoma-carcinoma transition.
  Gastroenterology, 137, 639.  
19619488 B.T.MacDonald, K.Tamai, and X.He (2009).
Wnt/beta-catenin signaling: components, mechanisms, and diseases.
  Dev Cell, 17, 9.  
19274088 C.L.Dahlberg, E.Z.Nguyen, D.Goodlett, and D.Kimelman (2009).
Interactions between Casein kinase Iepsilon (CKIepsilon) and two substrates from disparate signaling pathways reveal mechanisms for substrate-kinase specificity.
  PLoS ONE, 4, e4766.  
19520846 C.Y.Ou, J.H.Kim, C.K.Yang, and M.R.Stallcup (2009).
Requirement of Cell Cycle and Apoptosis Regulator 1 for Target Gene Activation by Wnt and {beta}-Catenin and for Anchorage-independent Growth of Human Colon Carcinoma Cells.
  J Biol Chem, 284, 20629-20637.  
19246243 D.P.Hanger, B.H.Anderton, and W.Noble (2009).
Tau phosphorylation: the therapeutic challenge for neurodegenerative disease.
  Trends Mol Med, 15, 112-119.  
19001380 G.V.Shah, A.Muralidharan, M.Gokulgandhi, K.Soan, and S.Thomas (2009).
Cadherin Switching and Activation of {beta}-Catenin Signaling Underlie Proinvasive Actions of Calcitonin-Calcitonin Receptor Axis in Prostate Cancer.
  J Biol Chem, 284, 1018-1030.  
  20066091 K.M.Cadigan, and M.Peifer (2009).
Wnt signaling from development to disease: insights from model systems.
  Cold Spring Harbor Perspect Biol, 1, a002881.  
19620634 M.T.Maher, A.S.Flozak, A.M.Stocker, A.Chenn, and C.J.Gottardi (2009).
Activity of the beta-catenin phosphodestruction complex at cell-cell contacts is enhanced by cadherin-based adhesion.
  J Cell Biol, 186, 219-228.  
19706613 R.Mo, T.L.Chew, M.T.Maher, G.Bellipanni, E.S.Weinberg, and C.J.Gottardi (2009).
The terminal region of beta-catenin promotes stability by shielding the Armadillo repeats from the axin-scaffold destruction complex.
  J Biol Chem, 284, 28222-28231.  
19525225 Y.Kawasaki, S.Tsuji, M.Sagara, K.Echizen, Y.Shibata, and T.Akiyama (2009).
Adenomatous polyposis coli and Asef function downstream of hepatocyte growth factor and phosphatidylinositol 3-kinase.
  J Biol Chem, 284, 22436-22443.  
  18196974 A.Han, C.Tong, D.Hu, X.Bi, and W.Yang (2008).
A direct protein-protein interaction is involved in the suppression of beta-catenin transcription by retinoid X receptor alpha in colorectal cancer cells.
  Cancer Biol Ther, 7, 454-459.  
18387324 A.I.Barth, H.Y.Caro-Gonzalez, and W.J.Nelson (2008).
Role of adenomatous polyposis coli (APC) and microtubules in directional cell migration and neuronal polarization.
  Semin Cell Dev Biol, 19, 245-251.  
19029934 A.Jeanes, C.J.Gottardi, and A.S.Yap (2008).
Cadherins and cancer: how does cadherin dysfunction promote tumor progression?
  Oncogene, 27, 6920-6929.  
18359618 B.M.McCartney, and I.S.Näthke (2008).
Cell regulation by the Apc protein Apc as master regulator of epithelia.
  Curr Opin Cell Biol, 20, 186-193.  
18387968 E.M.Kohler, A.Derungs, G.Daum, J.Behrens, and J.Schneikert (2008).
Functional definition of the mutation cluster region of adenomatous polyposis coli in colorectal tumours.
  Hum Mol Genet, 17, 1978-1987.  
18641688 G.Upadhyay, W.Goessling, T.E.North, R.Xavier, L.I.Zon, and V.Yajnik (2008).
Molecular association between beta-catenin degradation complex and Rac guanine exchange factor DOCK4 is essential for Wnt/beta-catenin signaling.
  Oncogene, 27, 5845-5855.  
18366741 J.Kitchen, R.E.Saunders, and J.Warwicker (2008).
Charge environments around phosphorylation sites in proteins.
  BMC Struct Biol, 8, 19.  
17968317 P.R.Rao, K.Makhijani, and L.S.Shashidhara (2008).
Human APC sequesters beta-catenin even in the absence of GSK-3beta in a Drosophila model.
  Oncogene, 27, 2488-2493.  
19107203 S.Piao, S.H.Lee, H.Kim, S.Yum, J.L.Stamos, Y.Xu, S.J.Lee, J.Lee, S.Oh, J.K.Han, B.J.Park, W.I.Weis, and N.C.Ha (2008).
Direct inhibition of GSK3beta by the phosphorylated cytoplasmic domain of LRP6 in Wnt/beta-catenin signaling.
  PLoS ONE, 3, e4046.  
18604449 X.Chen, J.Yang, P.M.Evans, and C.Liu (2008).
Wnt signaling: the good and the bad.
  Acta Biochim Biophys Sin (Shanghai), 40, 577-594.  
19061640 Y.Su, C.Fu, S.Ishikawa, A.Stella, M.Kojima, K.Shitoh, E.M.Schreiber, B.W.Day, and B.Liu (2008).
APC is essential for targeting phosphorylated beta-catenin to the SCFbeta-TrCP ubiquitin ligase.
  Mol Cell, 32, 652-661.  
17945476 D.L.Stokes (2007).
Desmosomes from a structural perspective.
  Curr Opin Cell Biol, 19, 565-571.  
18083923 D.Y.Dao, X.Yang, D.Chen, M.Zuscik, and R.J.O'Keefe (2007).
Axin1 and Axin2 are regulated by TGF- and mediate cross-talk between TGF- and Wnt signaling pathways.
  Ann N Y Acad Sci, 1116, 82-99.  
17072345 H.C.Huang, C.H.Hu, M.C.Tang, W.S.Wang, P.M.Chen, and Y.Su (2007).
Thymosin beta4 triggers an epithelial-mesenchymal transition in colorectal carcinoma by upregulating integrin-linked kinase.
  Oncogene, 26, 2781-2790.  
17768401 M.J.Nemeth, and D.M.Bodine (2007).
Regulation of hematopoiesis and the hematopoietic stem cell niche by Wnt signaling pathways.
  Cell Res, 17, 746-758.  
17660262 M.Ritco-Vonsovici, A.Ababou, and M.Horton (2007).
Molecular plasticity of beta-catenin: new insights from single-molecule measurements and MD simulation.
  Protein Sci, 16, 1984-1998.  
17189474 R.G.Garces, W.Gillon, and E.F.Pai (2007).
Atomic model of human Rcd-1 reveals an armadillo-like-repeat protein with in vitro nucleic acid binding properties.
  Protein Sci, 16, 176-188.
PDB code: 2fv2
17928543 R.L.Daugherty, and C.J.Gottardi (2007).
Phospho-regulation of Beta-catenin adhesion and signaling functions.
  Physiology (Bethesda), 22, 303-309.  
16401474 A.Vogel, J.E.Aslan, H.Willenbring, C.Klein, M.Finegold, H.Mount, G.Thomas, and M.Grompe (2006).
Sustained phosphorylation of Bid is a marker for resistance to Fas-induced apoptosis during chronic liver diseases.
  Gastroenterology, 130, 104-119.  
17143292 D.Kimelman, and W.Xu (2006).
beta-catenin destruction complex: insights and questions from a structural perspective.
  Oncogene, 25, 7482-7491.  
16705181 D.Tempé, M.Casas, S.Karaz, M.F.Blanchet-Tournier, and J.P.Concordet (2006).
Multisite protein kinase A and glycogen synthase kinase 3beta phosphorylation leads to Gli3 ubiquitination by SCFbetaTrCP.
  Mol Cell Biol, 26, 4316-4326.  
16293619 H.J.Choi, A.H.Huber, and W.I.Weis (2006).
Thermodynamics of beta-catenin-ligand interactions: the roles of the N- and C-terminal tails in modulating binding affinity.
  J Biol Chem, 281, 1027-1038.  
16880514 J.Dejmek, A.Säfholm, C.Kamp Nielsen, T.Andersson, and K.Leandersson (2006).
Wnt-5a/Ca2+-induced NFAT activity is counteracted by Wnt-5a/Yes-Cdc42-casein kinase 1alpha signaling in human mammary epithelial cells.
  Mol Cell Biol, 26, 6024-6036.  
16510874 J.Sierra, T.Yoshida, C.A.Joazeiro, and K.A.Jones (2006).
The APC tumor suppressor counteracts beta-catenin activation and H3K4 methylation at Wnt target genes.
  Genes Dev, 20, 586-600.  
16798748 J.Yang, W.Zhang, P.M.Evans, X.Chen, X.He, and C.Liu (2006).
Adenomatous polyposis coli (APC) differentially regulates beta-catenin phosphorylation and ubiquitination in colon cancer cells.
  J Biol Chem, 281, 17751-17757.  
16796800 S.V.Perryman, and K.G.Sylvester (2006).
Repair and regeneration: opportunities for carcinogenesis from tissue stem cells.
  J Cell Mol Med, 10, 292-308.  
16007186 M.A.Khaleque, A.Bharti, D.Sawyer, J.Gong, I.J.Benjamin, M.A.Stevenson, and S.K.Calderwood (2005).
Induction of heat shock proteins by heregulin beta1 leads to protection from apoptosis and anchorage-independent growth.
  Oncogene, 24, 6564-6573.  
15668160 M.Bienz (2005).
beta-Catenin: a pivot between cell adhesion and Wnt signalling.
  Curr Biol, 15, R64-R67.  
16051835 M.Fujimuro, J.Liu, J.Zhu, H.Yokosawa, and S.D.Hayward (2005).
Regulation of the interaction between glycogen synthase kinase 3 and the Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen.
  J Virol, 79, 10429-10441.  
15565646 P.Sobrado, A.Jedlicki, V.H.Bustos, C.C.Allende, and J.E.Allende (2005).
Basic region of residues 228-231 of protein kinase CK1alpha is involved in its interaction with axin: binding to axin does not affect the kinase activity.
  J Cell Biochem, 94, 217-224.  
15591320 R.Gail, R.Frank, and A.Wittinghofer (2005).
Systematic peptide array-based delineation of the differential beta-catenin interaction with Tcf4, E-cadherin, and adenomatous polyposis coli.
  J Biol Chem, 280, 7107-7117.  
15866026 T.J.Harris, and M.Peifer (2005).
Decisions, decisions: beta-catenin chooses between adhesion and transcription.
  Trends Cell Biol, 15, 234-237.  
15878878 X.M.Xu, Y.Q.Zhou, and M.H.Wang (2005).
Mechanisms of cytoplasmic {beta}-catenin accumulation and its involvement in tumorigenic activities mediated by oncogenic splicing variant of the receptor originated from Nantes tyrosine kinase.
  J Biol Chem, 280, 25087-25094.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.