2etx

From Proteopedia

(Difference between revisions)

Revision as of 12:29, 10 February 2021

Crystal Structure of MDC1 Tandem BRCT Domains

Structural highlights

2etx 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.
Gene:	MDC1 (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[MDC1_HUMAN] 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.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9] ^[10]

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

Microcephalin (MCPH1), the first gene identified as causative for primary recessive autosomal microcephaly, is aberrantly expressed in autism-like disorders and human malignancy of breast and ovarian origin. MCPH1, the encoded protein product, has been implicated in various cellular processes including the DNA damage checkpoint, DNA repair and transcription. While our understanding of the cellular context in which MCPH1 operates continues to develop, a structural understanding of the C-terminal tandem BRCT domains of MCPH1 remains unexplored. Here, we identify Cdc27, a component of the anaphase-promoting complex (APC/C), as a novel interacting partner of MCPH1. We provide in vitro and in vivo evidence that the C-terminal tandem BRCT domains of MCPH1 (C-BRCTs) bind Cdc27 in a phosphorylation-dependent manner. To further characterize this interaction, we determined the structure of MCPH1 C-BRCTs in complex with a phosphorylated Cdc27 peptide (pCdc27) using X-ray crystallography. Based on this structure, we identified single amino acid mutations targeted at the binding interface that disrupted the MCPH1-pCdc27 interaction. Collectively, our data define the biochemical, structural and cellular determinants of the novel interaction between MCPH1 and Cdc27 and suggest that this interaction may occur within the larger context of MCPH1-APC/C.

Molecular basis for the association of microcephalin (MCPH1) with the cell division cycle protein 27 (Cdc27) subunit of the anaphase-promoting complex.,Singh N, Wiltshire T, Thompson JR, Mer G, Couch FJ J Biol Chem. 2011 Dec 2. PMID:22139841^[11]

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

References

↑ Mochan TA, Venere M, DiTullio RA Jr, Halazonetis TD. 53BP1 and NFBD1/MDC1-Nbs1 function in parallel interacting pathways activating ataxia-telangiectasia mutated (ATM) in response to DNA damage. Cancer Res. 2003 Dec 15;63(24):8586-91. PMID:14695167
↑ Shang YL, Bodero AJ, Chen PL. NFBD1, a novel nuclear protein with signature motifs of FHA and BRCT, and an internal 41-amino acid repeat sequence, is an early participant in DNA damage response. J Biol Chem. 2003 Feb 21;278(8):6323-9. Epub 2002 Dec 9. PMID:12475977 doi:10.1074/jbc.M210749200
↑ Xu X, Stern DF. NFBD1/KIAA0170 is a chromatin-associated protein involved in DNA damage signaling pathways. J Biol Chem. 2003 Mar 7;278(10):8795-803. Epub 2002 Dec 23. PMID:12499369 doi:10.1074/jbc.M211392200
↑ Peng A, Chen PL. NFBD1, like 53BP1, is an early and redundant transducer mediating Chk2 phosphorylation in response to DNA damage. J Biol Chem. 2003 Mar 14;278(11):8873-6. Epub 2003 Jan 24. PMID:12551934 doi:10.1074/jbc.C300001200
↑ Lou Z, Chini CC, Minter-Dykhouse K, Chen J. Mediator of DNA damage checkpoint protein 1 regulates BRCA1 localization and phosphorylation in DNA damage checkpoint control. J Biol Chem. 2003 Apr 18;278(16):13599-602. Epub 2003 Feb 27. PMID:12611903 doi:10.1074/jbc.C300060200
↑ Goldberg M, Stucki M, Falck J, D'Amours D, Rahman D, Pappin D, Bartek J, Jackson SP. MDC1 is required for the intra-S-phase DNA damage checkpoint. Nature. 2003 Feb 27;421(6926):952-6. PMID:12607003 doi:10.1038/nature01445
↑ 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
↑ Stewart GS, Wang B, Bignell CR, Taylor AM, Elledge SJ. MDC1 is a mediator of the mammalian DNA damage checkpoint. Nature. 2003 Feb 27;421(6926):961-6. PMID:12607005 doi:10.1038/nature01446
↑ Lukas C, Melander F, Stucki M, Falck J, Bekker-Jensen S, Goldberg M, Lerenthal Y, Jackson SP, Bartek J, Lukas J. Mdc1 couples DNA double-strand break recognition by Nbs1 with its H2AX-dependent chromatin retention. EMBO J. 2004 Jul 7;23(13):2674-83. Epub 2004 Jun 17. PMID:15201865 doi:10.1038/sj.emboj.7600269
↑ Lou Z, Chen BP, Asaithamby A, Minter-Dykhouse K, Chen DJ, Chen J. MDC1 regulates DNA-PK autophosphorylation in response to DNA damage. J Biol Chem. 2004 Nov 5;279(45):46359-62. Epub 2004 Sep 17. PMID:15377652 doi:10.1074/jbc.C400375200
↑ Singh N, Wiltshire T, Thompson JR, Mer G, Couch FJ. Molecular basis for the association of microcephalin (MCPH1) with the cell division cycle protein 27 (Cdc27) subunit of the anaphase-promoting complex. J Biol Chem. 2011 Dec 2. PMID:22139841 doi:10.1074/jbc.M111.307868

1 Structural highlights
2 Function
3 Evolutionary Conservation
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2etx"

@@ Line 1: / Line 1: @@
 ==Crystal Structure of MDC1 Tandem BRCT Domains==
-<StructureSection load='2etx' size='340' side='right' caption='[[2etx]], [[Resolution|resolution]] 1.33&Aring;' scene=''>
+<StructureSection load='2etx' size='340' side='right'caption='[[2etx]], [[Resolution|resolution]] 1.33&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2etx]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2ETX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2ETX FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2etx]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2ETX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2ETX FirstGlance]. <br>
-</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MDC1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+</td></tr><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=9606 HUMAN])</td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2etx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2etx OCA], [http://pdbe.org/2etx PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2etx RCSB], [http://www.ebi.ac.uk/pdbsum/2etx PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2etx ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2etx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2etx OCA], [https://pdbe.org/2etx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2etx RCSB], [https://www.ebi.ac.uk/pdbsum/2etx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2etx ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/MDC1_HUMAN MDC1_HUMAN]] 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.<ref>PMID:14695167</ref> <ref>PMID:12475977</ref> <ref>PMID:12499369</ref> <ref>PMID:12551934</ref> <ref>PMID:12611903</ref> <ref>PMID:12607003</ref> <ref>PMID:12607004</ref> <ref>PMID:12607005</ref> <ref>PMID:15201865</ref> <ref>PMID:15377652</ref>
+[[https://www.uniprot.org/uniprot/MDC1_HUMAN MDC1_HUMAN]] 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.<ref>PMID:14695167</ref> <ref>PMID:12475977</ref> <ref>PMID:12499369</ref> <ref>PMID:12551934</ref> <ref>PMID:12611903</ref> <ref>PMID:12607003</ref> <ref>PMID:12607004</ref> <ref>PMID:12607005</ref> <ref>PMID:15201865</ref> <ref>PMID:15377652</ref>
 == Evolutionary Conservation ==
 [[Image:Consurf_key_small.gif|200px|right]]
@@ Line 33: / Line 33: @@
 </StructureSection>
 [[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Joachimiak, A]]
 [[Category: Kim, Y]]

2etx

From Proteopedia

Revision as of 12:29, 10 February 2021

Crystal Structure of MDC1 Tandem BRCT Domains

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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