1gxc

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FHA domain from human Chk2 kinase in complex with a synthetic phosphopeptide

Structural highlights

1gxc is a 8 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.7Å
Ligands:TPO
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

CHK2_HUMAN Defects in CHEK2 are associated with Li-Fraumeni syndrome 2 (LFS2) [MIM:609265; a highly penetrant familial cancer phenotype usually associated with inherited mutations in p53/TP53.[1] Defects in CHEK2 may be a cause of susceptibility to prostate cancer (PC) [MIM:176807. It is a malignancy originating in tissues of the prostate. Most prostate cancers are adenocarcinomas that develop in the acini of the prostatic ducts. Other rare histopathologic types of prostate cancer that occur in approximately 5% of patients include small cell carcinoma, mucinous carcinoma, prostatic ductal carcinoma, transitional cell carcinoma, squamous cell carcinoma, basal cell carcinoma, adenoid cystic carcinoma (basaloid), signet-ring cell carcinoma and neuroendocrine carcinoma. Defects in CHEK2 are found in some patients with osteogenic sarcoma (OSRC) [MIM:259500. Defects in CHEK2 is a cause of susceptibility to breast cancer (BC) [MIM:114480. A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case. Note=CHEK2 variants are associated with susceptibility to breast cancer and contribute to a substantial fraction of familial breast cancer (PubMed:12094328).[2] [3]

Function

CHK2_HUMAN Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest, activation of DNA repair and apoptosis in response to the presence of DNA double-strand breaks. May also negatively regulate cell cycle progression during unperturbed cell cycles. Following activation, phosphorylates numerous effectors preferentially at the consensus sequence [L-X-R-X-X-S/T]. Regulates cell cycle checkpoint arrest through phosphorylation of CDC25A, CDC25B and CDC25C, inhibiting their activity. Inhibition of CDC25 phosphatase activity leads to increased inhibitory tyrosine phosphorylation of CDK-cyclin complexes and blocks cell cycle progression. May also phosphorylate NEK6 which is involved in G2/M cell cycle arrest. Regulates DNA repair through phosphorylation of BRCA2, enhancing the association of RAD51 with chromatin which promotes DNA repair by homologous recombination. Also stimulates the transcription of genes involved in DNA repair (including BRCA2) through the phosphorylation and activation of the transcription factor FOXM1. Regulates apoptosis through the phosphorylation of p53/TP53, MDM4 and PML. Phosphorylation of p53/TP53 at 'Ser-20' by CHEK2 may alleviate inhibition by MDM2, leading to accumulation of active p53/TP53. Phosphorylation of MDM4 may also reduce degradation of p53/TP53. Also controls the transcription of pro-apoptotic genes through phosphorylation of the transcription factor E2F1. Tumor suppressor, it may also have a DNA damage-independent function in mitotic spindle assembly by phosphorylating BRCA1. Its absence may be a cause of the chromosomal instability observed in some cancer cells.[4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

The Chk2 Ser/Thr kinase plays crucial, evolutionarily conserved roles in cellular responses to DNA damage. Identification of two pro-oncogenic mutations within the Chk2 FHA domain has highlighted its importance for Chk2 function in checkpoint activation. The X-ray structure of the Chk2 FHA domain in complex with an in vitro selected phosphopeptide motif reveals the determinants of binding specificity and shows that both mutations are remote from the peptide binding site. We show that the Chk2 FHA domain mediates ATM-dependent Chk2 phosphorylation and targeting of Chk2 to in vivo binding partners such as BRCA1 through either or both of two structurally distinct mechanisms. Although phospho-dependent binding is important for Chk2 activity, previously uncharacterized phospho-independent FHA domain interactions appear to be the primary target of oncogenic lesions.

Structural and functional versatility of the FHA domain in DNA-damage signaling by the tumor suppressor kinase Chk2.,Li J, Williams BL, Haire LF, Goldberg M, Wilker E, Durocher D, Yaffe MB, Jackson SP, Smerdon SJ Mol Cell. 2002 May;9(5):1045-54. PMID:12049740[21]

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

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Citations
29 reviews cite this structure
Chk1 and Chk2 kinases in checkpoint control and cancer.
Bartek et al. (2003)
28 more
108 other articles
No citations found

See Also

References

  1. ↑ Lee SB, Kim SH, Bell DW, Wahrer DC, Schiripo TA, Jorczak MM, Sgroi DC, Garber JE, Li FP, Nichols KE, Varley JM, Godwin AK, Shannon KM, Harlow E, Haber DA. Destabilization of CHK2 by a missense mutation associated with Li-Fraumeni Syndrome. Cancer Res. 2001 Nov 15;61(22):8062-7. PMID:11719428
  2. ↑ Vahteristo P, Bartkova J, Eerola H, Syrjakoski K, Ojala S, Kilpivaara O, Tamminen A, Kononen J, Aittomaki K, Heikkila P, Holli K, Blomqvist C, Bartek J, Kallioniemi OP, Nevanlinna H. A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer. Am J Hum Genet. 2002 Aug;71(2):432-8. Epub 2002 Jul 28. PMID:12094328 doi:10.1086/341943
  3. ↑ Liu Y, Liao J, Xu Y, Chen W, Liu D, Ouyang T, Li J, Wang T, Fan Z, Fan T, Lin B, Xu X, Xie Y. A recurrent CHEK2 p.H371Y mutation is associated with breast cancer risk in Chinese women. Hum Mutat. 2011 May 26. doi: 10.1002/humu.21538. PMID:21618645 doi:10.1002/humu.21538
  4. ↑ Matsuoka S, Huang M, Elledge SJ. Linkage of ATM to cell cycle regulation by the Chk2 protein kinase. Science. 1998 Dec 4;282(5395):1893-7. PMID:9836640
  5. ↑ Blasina A, de Weyer IV, Laus MC, Luyten WH, Parker AE, McGowan CH. A human homologue of the checkpoint kinase Cds1 directly inhibits Cdc25 phosphatase. Curr Biol. 1999 Jan 14;9(1):1-10. PMID:9889122
  6. ↑ Brown AL, Lee CH, Schwarz JK, Mitiku N, Piwnica-Worms H, Chung JH. A human Cds1-related kinase that functions downstream of ATM protein in the cellular response to DNA damage. Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3745-50. PMID:10097108
  7. ↑ Lee JS, Collins KM, Brown AL, Lee CH, Chung JH. hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response. Nature. 2000 Mar 9;404(6774):201-4. PMID:10724175 doi:10.1038/35004614
  8. ↑ Falck J, Mailand N, Syljuasen RG, Bartek J, Lukas J. The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis. Nature. 2001 Apr 12;410(6830):842-7. PMID:11298456 doi:10.1038/35071124
  9. ↑ Yang S, Kuo C, Bisi JE, Kim MK. PML-dependent apoptosis after DNA damage is regulated by the checkpoint kinase hCds1/Chk2. Nat Cell Biol. 2002 Nov;4(11):865-70. PMID:12402044 doi:10.1038/ncb869
  10. ↑ Louria-Hayon I, Grossman T, Sionov RV, Alsheich O, Pandolfi PP, Haupt Y. The promyelocytic leukemia protein protects p53 from Mdm2-mediated inhibition and degradation. J Biol Chem. 2003 Aug 29;278(35):33134-41. Epub 2003 Jun 16. PMID:12810724 doi:10.1074/jbc.M301264200
  11. ↑ Stevens C, Smith L, La Thangue NB. Chk2 activates E2F-1 in response to DNA damage. Nat Cell Biol. 2003 May;5(5):401-9. PMID:12717439 doi:10.1038/ncb974
  12. ↑ Lou Z, Minter-Dykhouse K, Wu X, Chen J. MDC1 is coupled to activated CHK2 in mammalian DNA damage response pathways. Nature. 2003 Feb 27;421(6926):957-61. PMID:12607004 doi:10.1038/nature01447
  13. ↑ Chen L, Gilkes DM, Pan Y, Lane WS, Chen J. ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage. EMBO J. 2005 Oct 5;24(19):3411-22. Epub 2005 Sep 15. PMID:16163388 doi:10.1038/sj.emboj.7600812
  14. ↑ Inoue Y, Kitagawa M, Taya Y. Phosphorylation of pRB at Ser612 by Chk1/2 leads to a complex between pRB and E2F-1 after DNA damage. EMBO J. 2007 Apr 18;26(8):2083-93. Epub 2007 Mar 22. PMID:17380128 doi:10.1038/sj.emboj.7601652
  15. ↑ Kass EM, Ahn J, Tanaka T, Freed-Pastor WA, Keezer S, Prives C. Stability of checkpoint kinase 2 is regulated via phosphorylation at serine 456. J Biol Chem. 2007 Oct 12;282(41):30311-21. Epub 2007 Aug 21. PMID:17715138 doi:10.1074/jbc.M704642200
  16. ↑ Tan Y, Raychaudhuri P, Costa RH. Chk2 mediates stabilization of the FoxM1 transcription factor to stimulate expression of DNA repair genes. Mol Cell Biol. 2007 Feb;27(3):1007-16. Epub 2006 Nov 13. PMID:17101782 doi:10.1128/MCB.01068-06
  17. ↑ Lee MY, Kim HJ, Kim MA, Jee HJ, Kim AJ, Bae YS, Park JI, Chung JH, Yun J. Nek6 is involved in G2/M phase cell cycle arrest through DNA damage-induced phosphorylation. Cell Cycle. 2008 Sep 1;7(17):2705-9. Epub 2008 Sep 3. PMID:18728393
  18. ↑ Lovly CM, Yan L, Ryan CE, Takada S, Piwnica-Worms H. Regulation of Chk2 ubiquitination and signaling through autophosphorylation of serine 379. Mol Cell Biol. 2008 Oct;28(19):5874-85. doi: 10.1128/MCB.00821-08. Epub 2008 Jul , 21. PMID:18644861 doi:10.1128/MCB.00821-08
  19. ↑ Bahassi EM, Ovesen JL, Riesenberg AL, Bernstein WZ, Hasty PE, Stambrook PJ. The checkpoint kinases Chk1 and Chk2 regulate the functional associations between hBRCA2 and Rad51 in response to DNA damage. Oncogene. 2008 Jun 26;27(28):3977-85. doi: 10.1038/onc.2008.17. Epub 2008 Mar 3. PMID:18317453 doi:10.1038/onc.2008.17
  20. ↑ Stolz A, Ertych N, Kienitz A, Vogel C, Schneider V, Fritz B, Jacob R, Dittmar G, Weichert W, Petersen I, Bastians H. The CHK2-BRCA1 tumour suppressor pathway ensures chromosomal stability in human somatic cells. Nat Cell Biol. 2010 May;12(5):492-9. doi: 10.1038/ncb2051. Epub 2010 Apr 4. PMID:20364141 doi:10.1038/ncb2051
  21. ↑ Li J, Williams BL, Haire LF, Goldberg M, Wilker E, Durocher D, Yaffe MB, Jackson SP, Smerdon SJ. Structural and functional versatility of the FHA domain in DNA-damage signaling by the tumor suppressor kinase Chk2. Mol Cell. 2002 May;9(5):1045-54. PMID:12049740

Contents


PDB ID 1gxc

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