3va4

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[[Image:3va4.jpg|left|200px]]
 
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==Crystal structure of the mammalian MDC1 FHA domain complexed with CHK2 pThr68 peptide==
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The line below this paragraph, containing "STRUCTURE_3va4", creates the "Structure Box" on the page.
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<StructureSection load='3va4' size='340' side='right'caption='[[3va4]], [[Resolution|resolution]] 1.54&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[3va4]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3VA4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3VA4 FirstGlance]. <br>
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</td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3va1|3va1]]</div></td></tr>
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{{STRUCTURE_3va4| PDB=3va4 | SCENE= }}
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MDC1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3va4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3va4 OCA], [https://pdbe.org/3va4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3va4 RCSB], [https://www.ebi.ac.uk/pdbsum/3va4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3va4 ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[[https://www.uniprot.org/uniprot/CHK2_HUMAN CHK2_HUMAN]] Defects in CHEK2 are associated with Li-Fraumeni syndrome 2 (LFS2) [MIM:[https://omim.org/entry/609265 609265]]; a highly penetrant familial cancer phenotype usually associated with inherited mutations in p53/TP53.<ref>PMID:11719428</ref> Defects in CHEK2 may be a cause of susceptibility to prostate cancer (PC) [MIM:[https://omim.org/entry/176807 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:[https://omim.org/entry/259500 259500]]. Defects in CHEK2 is a cause of susceptibility to breast cancer (BC) [MIM:[https://omim.org/entry/114480 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).<ref>PMID:12094328</ref> <ref>PMID:21618645</ref>
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== Function ==
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[[https://www.uniprot.org/uniprot/MDC1_MOUSE MDC1_MOUSE]] Required for checkpoint mediated cell cycle arrest in response to DNA damage within both the S phase and G2/M phases of the cell cycle. May serve as a scaffold for the recruitment of DNA repair and signal transduction proteins to discrete foci of DNA damage marked by 'Ser-139' phosphorylation of histone H2AFX. Also required for downstream events subsequent to the recruitment of these proteins. These include phosphorylation and activation of the ATM, CHEK1 and CHEK2 kinases, and stabilization of TP53 and apoptosis. ATM and CHEK2 may also be activated independently by a parallel pathway mediated by TP53BP1 (By similarity). [[https://www.uniprot.org/uniprot/CHK2_HUMAN 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.<ref>PMID:9836640</ref> <ref>PMID:9889122</ref> <ref>PMID:10097108</ref> <ref>PMID:10724175</ref> <ref>PMID:11298456</ref> <ref>PMID:12402044</ref> <ref>PMID:12810724</ref> <ref>PMID:12717439</ref> <ref>PMID:12607004</ref> <ref>PMID:16163388</ref> <ref>PMID:17380128</ref> <ref>PMID:17715138</ref> <ref>PMID:17101782</ref> <ref>PMID:18728393</ref> <ref>PMID:18644861</ref> <ref>PMID:18317453</ref> <ref>PMID:20364141</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Mammalian MDC1 interacts with CHK2 in the regulation of DNA damage-induced S-phase checkpoint and apoptosis, which is directed by the association of MDC1-FHA and CHK2-pThr68. However, different ligand specificities of MDC1-FHA have been reported, and no structure is available. Here we report the crystal structures of MDC1-FHA and its complex with a CHK2 peptide containing pThr68. Unlike other FHA domains, MDC1-FHA exists as an intrinsic dimer in solution and in crystals. Structural and binding analyses support pThr+3 ligand specificity and provide structural insight into MDC1-CHK2 interaction.
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===Crystal structure of the mammalian MDC1 FHA domain complexed with CHK2 pThr68 peptide===
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Structural Delineation of MDC1-FHA Domain Binding with CHK2-pThr68.,Wu HH, Wu PY, Huang KF, Kao YY, Tsai MD Biochemistry. 2012 Jan 17;51(2):575-7. Epub 2012 Jan 6. PMID:22211259<ref>PMID:22211259</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 3va4" style="background-color:#fffaf0;"></div>
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(as it appears on PubMed at http://www.pubmed.gov), where 22211259 is the PubMed ID number.
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== References ==
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<references/>
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{{ABSTRACT_PUBMED_22211259}}
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__TOC__
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</StructureSection>
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==About this Structure==
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[[Category: Large Structures]]
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[[3va4]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3VA4 OCA].
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[[Category: Lk3 transgenic mice]]
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[[Category: Huang, K F]]
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==Reference==
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[[Category: Kao, Y Y]]
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<ref group="xtra">PMID:022211259</ref><references group="xtra"/>
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[[Category: Tsai, M D]]
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[[Category: Mus musculus]]
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[[Category: Wu, H H]]
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[[Category: Huang, K F.]]
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[[Category: Wu, P Y]]
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[[Category: Kao, Y Y.]]
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[[Category: Tsai, M D.]]
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[[Category: Wu, H H.]]
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[[Category: Wu, P Y.]]
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[[Category: Cell cycle]]
[[Category: Cell cycle]]
[[Category: Chk2 and mdc1 dimerization]]
[[Category: Chk2 and mdc1 dimerization]]
[[Category: Dna-damage]]
[[Category: Dna-damage]]
[[Category: Fha domain]]
[[Category: Fha domain]]

Current revision

Crystal structure of the mammalian MDC1 FHA domain complexed with CHK2 pThr68 peptide

PDB ID 3va4

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