4nm3

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Crystal structure of GSK-3/Axin complex bound to phosphorylated N-terminal auto-inhibitory pS9 peptideCrystal structure of GSK-3/Axin complex bound to phosphorylated N-terminal auto-inhibitory pS9 peptide

Structural highlights

4nm3 is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:, , , ,
NonStd Res:
Gene:GSK3B (HUMAN), AXIN, AXIN1 (HUMAN)
Resources:FirstGlance, OCA, RCSB, PDBsum

Disease

[AXIN1_HUMAN] Defects in AXIN1 are involved in hepatocellular carcinoma (HCC) [MIM:114550].[1] [2] Defects in AXIN1 are a cause of caudal duplication anomaly (CADUA) [MIM:607864]. Caudal duplication anomaly is characterized by the occurrence of duplications of different organs in the caudal region. Note=Caudal duplication anomaly is associated with hypermethylation of the AXIN1 promoter.[3]

Function

[GSK3B_HUMAN] Constitutively active protein kinase that acts as a negative regulator in the hormonal control of glucose homeostasis, Wnt signaling and regulation of transcription factors and microtubules, by phosphorylating and inactivating glycogen synthase (GYS1 or GYS2), EIF2B, CTNNB1/beta-catenin, APC, AXIN1, DPYSL2/CRMP2, JUN, NFATC1/NFATC, MAPT/TAU and MACF1. Requires primed phosphorylation of the majority of its substrates. In skeletal muscle, contributes to insulin regulation of glycogen synthesis by phosphorylating and inhibiting GYS1 activity and hence glycogen synthesis. May also mediate the development of insulin resistance by regulating activation of transcription factors. Regulates protein synthesis by controlling the activity of initiation factor 2B (EIF2BE/EIF2B5) in the same manner as glycogen synthase. In Wnt signaling, GSK3B forms a multimeric complex with APC, AXIN1 and CTNNB1/beta-catenin and phosphorylates the N-terminus of CTNNB1 leading to its degradation mediated by ubiquitin/proteasomes. Phosphorylates JUN at sites proximal to its DNA-binding domain, thereby reducing its affinity for DNA. Phosphorylates NFATC1/NFATC on conserved serine residues promoting NFATC1/NFATC nuclear export, shutting off NFATC1/NFATC gene regulation, and thereby opposing the action of calcineurin. Phosphorylates MAPT/TAU on 'Thr-548', decreasing significantly MAPT/TAU ability to bind and stabilize microtubules. MAPT/TAU is the principal component of neurofibrillary tangles in Alzheimer disease. Plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex. Phosphorylates MACF1, inhibiting its binding to microtubules which is critical for its role in bulge stem cell migration and skin wound repair. Probably regulates NF-kappa-B (NFKB1) at the transcriptional level and is required for the NF-kappa-B-mediated anti-apoptotic response to TNF-alpha (TNF/TNFA). Negatively regulates replication in pancreatic beta-cells, resulting in apoptosis, loss of beta-cells and diabetes. Phosphorylates MUC1 in breast cancer cells, decreasing the interaction of MUC1 with CTNNB1/beta-catenin. Is necessary for the establishment of neuronal polarity and axon outgrowth. Phosphorylates MARK2, leading to inhibit its activity. Phosphorylates SIK1 at 'Thr-182', leading to sustain its activity. Phosphorylates ZC3HAV1 which enhances its antiviral activity. Phosphorylates SFPQ at 'Thr-687' upon T-cell activation.[4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [AXIN1_HUMAN] Component of the beta-catenin destruction complex required for regulating CTNNB1 levels through phosphorylation and ubiquitination, and modulating Wnt-signaling. Controls dorsoventral patterning via two opposing effects; down-regulates CTNNB1 to inhibit the Wnt signaling pathway and ventralize embryos, but also dorsalizes embryos by activating a Wnt-independent JNK signaling pathway. In Wnt signaling, probably facilitates the phosphorylation of CTNNB1 and APC by GSK3B. Likely to function as a tumor suppressor. Facilitates the phosphorylation of TP53 by HIPK2 upon ultraviolet irradiation. Enhances TGF-beta signaling by recruiting the RNF111 E3 ubiquitin ligase and promoting the degradation of inhibitory SMAD7. Also component of the AXIN1-HIPK2-TP53 complex which controls cell growth, apoptosis and development.[16] [17] [18]

Publication Abstract from PubMed

Glycogen synthase kinase-3 (GSK-3) is a key regulator of many cellular signaling pathways. Unlike most kinases, GSK-3 is controlled by inhibition rather than by specific activation. In the insulin and several other signaling pathways, phosphorylation of a serine present in a conserved sequence near the amino terminus of GSK-3 generates an auto-inhibitory peptide. In contrast, Wnt/beta-catenin signal transduction requires phosphorylation of Ser/Pro rich sequences present in the Wnt co-receptors LRP5/6, and these motifs inhibit GSK-3 activity. We present crystal structures of GSK-3 bound to its phosphorylated N-terminus and to two of the phosphorylated LRP6 motifs. A conserved loop unique to GSK-3 undergoes a dramatic conformational change that clamps the bound pseudo-substrate peptides, and reveals the mechanism of primed substrate recognition. The structures rationalize target sequence preferences and suggest avenues for the design of inhibitors selective for a subset of pathways regulated by GSK-3. DOI: http://dx.doi.org/10.7554/eLife.01998.001.

Structural basis of GSK-3 inhibition by N-terminal phosphorylation and by the Wnt receptor LRP6.,Stamos JL, Chu ML, Enos MD, Shah N, Weis WI Elife. 2014 Mar 18;3:e01998. doi: 10.7554/eLife.01998. PMID:24642411[19]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Satoh S, Daigo Y, Furukawa Y, Kato T, Miwa N, Nishiwaki T, Kawasoe T, Ishiguro H, Fujita M, Tokino T, Sasaki Y, Imaoka S, Murata M, Shimano T, Yamaoka Y, Nakamura Y. AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1. Nat Genet. 2000 Mar;24(3):245-50. PMID:10700176 doi:10.1038/73448
  2. ↑ Taniguchi K, Roberts LR, Aderca IN, Dong X, Qian C, Murphy LM, Nagorney DM, Burgart LJ, Roche PC, Smith DI, Ross JA, Liu W. Mutational spectrum of beta-catenin, AXIN1, and AXIN2 in hepatocellular carcinomas and hepatoblastomas. Oncogene. 2002 Jul 18;21(31):4863-71. PMID:12101426 doi:10.1038/sj.onc.1205591
  3. ↑ Satoh S, Daigo Y, Furukawa Y, Kato T, Miwa N, Nishiwaki T, Kawasoe T, Ishiguro H, Fujita M, Tokino T, Sasaki Y, Imaoka S, Murata M, Shimano T, Yamaoka Y, Nakamura Y. AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1. Nat Genet. 2000 Mar;24(3):245-50. PMID:10700176 doi:10.1038/73448
  4. ↑ Boyle WJ, Smeal T, Defize LH, Angel P, Woodgett JR, Karin M, Hunter T. Activation of protein kinase C decreases phosphorylation of c-Jun at sites that negatively regulate its DNA-binding activity. Cell. 1991 Feb 8;64(3):573-84. PMID:1846781
  5. ↑ Welsh GI, Proud CG. Glycogen synthase kinase-3 is rapidly inactivated in response to insulin and phosphorylates eukaryotic initiation factor eIF-2B. Biochem J. 1993 Sep 15;294 ( Pt 3):625-9. PMID:8397507
  6. ↑ Beals CR, Sheridan CM, Turck CW, Gardner P, Crabtree GR. Nuclear export of NF-ATc enhanced by glycogen synthase kinase-3. Science. 1997 Mar 28;275(5308):1930-4. PMID:9072970
  7. ↑ Li Y, Bharti A, Chen D, Gong J, Kufe D. Interaction of glycogen synthase kinase 3beta with the DF3/MUC1 carcinoma-associated antigen and beta-catenin. Mol Cell Biol. 1998 Dec;18(12):7216-24. PMID:9819408
  8. ↑ Frame S, Cohen P, Biondi RM. A common phosphate binding site explains the unique substrate specificity of GSK3 and its inactivation by phosphorylation. Mol Cell. 2001 Jun;7(6):1321-7. PMID:11430833
  9. ↑ Cho JH, Johnson GV. Primed phosphorylation of tau at Thr231 by glycogen synthase kinase 3beta (GSK3beta) plays a critical role in regulating tau's ability to bind and stabilize microtubules. J Neurochem. 2004 Jan;88(2):349-58. PMID:14690523
  10. ↑ Zhou BP, Deng J, Xia W, Xu J, Li YM, Gunduz M, Hung MC. Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat Cell Biol. 2004 Oct;6(10):931-40. Epub 2004 Sep 26. PMID:15448698 doi:10.1038/ncb1173
  11. ↑ Hashimoto YK, Satoh T, Okamoto M, Takemori H. Importance of autophosphorylation at Ser186 in the A-loop of salt inducible kinase 1 for its sustained kinase activity. J Cell Biochem. 2008 Aug 1;104(5):1724-39. doi: 10.1002/jcb.21737. PMID:18348280 doi:10.1002/jcb.21737
  12. ↑ Heyd F, Lynch KW. Phosphorylation-dependent regulation of PSF by GSK3 controls CD45 alternative splicing. Mol Cell. 2010 Oct 8;40(1):126-37. doi: 10.1016/j.molcel.2010.09.013. PMID:20932480 doi:10.1016/j.molcel.2010.09.013
  13. ↑ Zaoui K, Benseddik K, Daou P, Salaun D, Badache A. ErbB2 receptor controls microtubule capture by recruiting ACF7 to the plasma membrane of migrating cells. Proc Natl Acad Sci U S A. 2010 Oct 26;107(43):18517-22. doi:, 10.1073/pnas.1000975107. Epub 2010 Oct 11. PMID:20937854 doi:10.1073/pnas.1000975107
  14. ↑ Sun L, Lv F, Guo X, Gao G. Glycogen synthase kinase 3beta (GSK3beta) modulates antiviral activity of zinc-finger antiviral protein (ZAP). J Biol Chem. 2012 Jun 29;287(27):22882-8. doi: 10.1074/jbc.M111.306373. Epub 2012, Apr 18. PMID:22514281 doi:10.1074/jbc.M111.306373
  15. ↑ Dajani R, Fraser E, Roe SM, Yeo M, Good VM, Thompson V, Dale TC, Pearl LH. Structural basis for recruitment of glycogen synthase kinase 3beta to the axin-APC scaffold complex. EMBO J. 2003 Feb 3;22(3):494-501. PMID:12554650 doi:10.1093/emboj/cdg068
  16. ↑ Kusano S, Raab-Traub N. I-mfa domain proteins interact with Axin and affect its regulation of the Wnt and c-Jun N-terminal kinase signaling pathways. Mol Cell Biol. 2002 Sep;22(18):6393-405. PMID:12192039
  17. ↑ Liu W, Rui H, Wang J, Lin S, He Y, Chen M, Li Q, Ye Z, Zhang S, Chan SC, Chen YG, Han J, Lin SC. Axin is a scaffold protein in TGF-beta signaling that promotes degradation of Smad7 by Arkadia. EMBO J. 2006 Apr 19;25(8):1646-58. Epub 2006 Apr 6. PMID:16601693 doi:7601057
  18. ↑ Li Q, Wang X, Wu X, Rui Y, Liu W, Wang J, Wang X, Liou YC, Ye Z, Lin SC. Daxx cooperates with the Axin/HIPK2/p53 complex to induce cell death. Cancer Res. 2007 Jan 1;67(1):66-74. PMID:17210684 doi:10.1158/0008-5472.CAN-06-1671
  19. ↑ Stamos JL, Chu ML, Enos MD, Shah N, Weis WI. Structural basis of GSK-3 inhibition by N-terminal phosphorylation and by the Wnt receptor LRP6. Elife. 2014 Mar 18;3:e01998. doi: 10.7554/eLife.01998. PMID:24642411

4nm3, resolution 2.10Å

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