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==Crystal Structure of TopBP1 BRCT7/8-BACH1 peptide complex==
==Crystal Structure of TopBP1 BRCT7/8-BACH1 peptide complex==
<StructureSection load='3al3' size='340' side='right' caption='[[3al3]], [[Resolution|resolution]] 2.15&Aring;' scene=''>
<StructureSection load='3al3' size='340' side='right'caption='[[3al3]], [[Resolution|resolution]] 2.15&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[3al3]] 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=3AL3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3AL3 FirstGlance]. <br>
<table><tr><td colspan='2'>[[3al3]] 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=3AL3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3AL3 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene></td></tr>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene></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>
<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>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3al2|3al2]]</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3al2|3al2]]</div></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">KIAA0259, TOPBP1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">KIAA0259, TOPBP1 ([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=3al3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3al3 OCA], [http://pdbe.org/3al3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3al3 RCSB], [http://www.ebi.ac.uk/pdbsum/3al3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3al3 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=3al3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3al3 OCA], [https://pdbe.org/3al3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3al3 RCSB], [https://www.ebi.ac.uk/pdbsum/3al3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3al3 ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
[[http://www.uniprot.org/uniprot/FANCJ_HUMAN FANCJ_HUMAN]] Defects in BRIP1 are a cause of susceptibility to breast cancer (BC) [MIM:[http://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.<ref>PMID:11301010</ref> <ref>PMID:14983014</ref> <ref>PMID:16153896</ref> <ref>PMID:16116421</ref>  Defects in BRIP1 are the cause of Fanconi anemia complementation group J (FANCJ) [MIM:[http://omim.org/entry/609054 609054]]. It is a disorder affecting all bone marrow elements and resulting in anemia, leukopenia and thrombopenia. It is associated with cardiac, renal and limb malformations, dermal pigmentary changes, and a predisposition to the development of malignancies. At the cellular level it is associated with hypersensitivity to DNA-damaging agents, chromosomal instability (increased chromosome breakage) and defective DNA repair.<ref>PMID:16153896</ref> <ref>PMID:16116421</ref> <ref>PMID:20639400</ref> <ref>PMID:16116424</ref> <ref>PMID:16116423</ref>   
[[https://www.uniprot.org/uniprot/FANCJ_HUMAN FANCJ_HUMAN]] Defects in BRIP1 are 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.<ref>PMID:11301010</ref> <ref>PMID:14983014</ref> <ref>PMID:16153896</ref> <ref>PMID:16116421</ref>  Defects in BRIP1 are the cause of Fanconi anemia complementation group J (FANCJ) [MIM:[https://omim.org/entry/609054 609054]]. It is a disorder affecting all bone marrow elements and resulting in anemia, leukopenia and thrombopenia. It is associated with cardiac, renal and limb malformations, dermal pigmentary changes, and a predisposition to the development of malignancies. At the cellular level it is associated with hypersensitivity to DNA-damaging agents, chromosomal instability (increased chromosome breakage) and defective DNA repair.<ref>PMID:16153896</ref> <ref>PMID:16116421</ref> <ref>PMID:20639400</ref> <ref>PMID:16116424</ref> <ref>PMID:16116423</ref>   
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/TOPB1_HUMAN TOPB1_HUMAN]] Required for DNA replication. Plays a role in the rescue of stalled replication forks and checkpoint control. Binds double-stranded DNA breaks and nicks as well as single-stranded DNA. Recruits the SWI/SNF chromatin remodeling complex to E2F1-responsive promoters. Down-regulates E2F1 activity and inhibits E2F1-dependent apoptosis during G1/S transition and after DNA damage. Induces a large increase in the kinase activity of ATR.<ref>PMID:10498869</ref> <ref>PMID:11395493</ref> <ref>PMID:11714696</ref> <ref>PMID:12697828</ref> <ref>PMID:15075294</ref> <ref>PMID:16530042</ref>  [[http://www.uniprot.org/uniprot/FANCJ_HUMAN FANCJ_HUMAN]] DNA-dependent ATPase and 5' to 3' DNA helicase required for the maintenance of chromosomal stability. Acts late in the Fanconi anemia pathway, after FANCD2 ubiquitination. Involved in the repair of DNA double-strand breaks by homologous recombination in a manner that depends on its association with BRCA1.<ref>PMID:11301010</ref> <ref>PMID:14983014</ref> <ref>PMID:16153896</ref> <ref>PMID:16116421</ref>   
[[https://www.uniprot.org/uniprot/TOPB1_HUMAN TOPB1_HUMAN]] Required for DNA replication. Plays a role in the rescue of stalled replication forks and checkpoint control. Binds double-stranded DNA breaks and nicks as well as single-stranded DNA. Recruits the SWI/SNF chromatin remodeling complex to E2F1-responsive promoters. Down-regulates E2F1 activity and inhibits E2F1-dependent apoptosis during G1/S transition and after DNA damage. Induces a large increase in the kinase activity of ATR.<ref>PMID:10498869</ref> <ref>PMID:11395493</ref> <ref>PMID:11714696</ref> <ref>PMID:12697828</ref> <ref>PMID:15075294</ref> <ref>PMID:16530042</ref>  [[https://www.uniprot.org/uniprot/FANCJ_HUMAN FANCJ_HUMAN]] DNA-dependent ATPase and 5' to 3' DNA helicase required for the maintenance of chromosomal stability. Acts late in the Fanconi anemia pathway, after FANCD2 ubiquitination. Involved in the repair of DNA double-strand breaks by homologous recombination in a manner that depends on its association with BRCA1.<ref>PMID:11301010</ref> <ref>PMID:14983014</ref> <ref>PMID:16153896</ref> <ref>PMID:16116421</ref>   
<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
Line 31: Line 31:
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Glover, J N]]
[[Category: Glover, J N]]
[[Category: Leung, C C]]
[[Category: Leung, C C]]
[[Category: Brct domain-phosphopeptide complex]]
[[Category: Brct domain-phosphopeptide complex]]
[[Category: Dna binding protein-protein binding complex]]
[[Category: Dna binding protein-protein binding complex]]

Revision as of 17:56, 29 December 2021

Crystal Structure of TopBP1 BRCT7/8-BACH1 peptide complexCrystal Structure of TopBP1 BRCT7/8-BACH1 peptide complex

Structural highlights

3al3 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:KIAA0259, TOPBP1 (HUMAN)
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[FANCJ_HUMAN] Defects in BRIP1 are 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.[1] [2] [3] [4] Defects in BRIP1 are the cause of Fanconi anemia complementation group J (FANCJ) [MIM:609054]. It is a disorder affecting all bone marrow elements and resulting in anemia, leukopenia and thrombopenia. It is associated with cardiac, renal and limb malformations, dermal pigmentary changes, and a predisposition to the development of malignancies. At the cellular level it is associated with hypersensitivity to DNA-damaging agents, chromosomal instability (increased chromosome breakage) and defective DNA repair.[5] [6] [7] [8] [9]

Function

[TOPB1_HUMAN] Required for DNA replication. Plays a role in the rescue of stalled replication forks and checkpoint control. Binds double-stranded DNA breaks and nicks as well as single-stranded DNA. Recruits the SWI/SNF chromatin remodeling complex to E2F1-responsive promoters. Down-regulates E2F1 activity and inhibits E2F1-dependent apoptosis during G1/S transition and after DNA damage. Induces a large increase in the kinase activity of ATR.[10] [11] [12] [13] [14] [15] [FANCJ_HUMAN] DNA-dependent ATPase and 5' to 3' DNA helicase required for the maintenance of chromosomal stability. Acts late in the Fanconi anemia pathway, after FANCD2 ubiquitination. Involved in the repair of DNA double-strand breaks by homologous recombination in a manner that depends on its association with BRCA1.[16] [17] [18] [19]

Publication Abstract from PubMed

The diverse roles of TopBP1 in DNA replication and checkpoint signaling are associated with the scaffolding ability of TopBP1 to initiate various protein-protein interactions. The recognition of the BACH1/FANCJ helicase by TopBP1 is critical for the activation of the DNA replication checkpoint at stalled replication forks and is facilitated by the C-terminal tandem BRCT7/8 domains of TopBP1 and a phosphorylated Thr(1133) binding motif in BACH1. Here we provide the structural basis for this interaction through analysis of the x-ray crystal structures of TopBP1 BRCT7/8 both free and in complex with a BACH1 phospho-peptide. In contrast to canonical BRCT-phospho-peptide recognition, TopBP1 BRCT7/8 undergoes a dramatic conformational change upon BACH1 binding such that the two BRCT repeats pivot about the central BRCT-BRCT interface to provide an extensive and deep peptide-binding cleft. Additionally, we provide the first structural mechanism for Thr(P) recognition among BRCT domains. Together with systematic mutagenesis studies, we highlight the role of key contacts in governing the unique specificity of the TopBP1-BACH1 interaction.

Molecular basis of BACH1/FANCJ recognition by TopBP1 in DNA replication checkpoint control.,Leung CC, Gong Z, Chen J, Glover JN J Biol Chem. 2011 Feb 11;286(6):4292-301. Epub 2010 Dec 2. PMID:21127055[20]

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

See Also

References

  1. ↑ Cantor SB, Bell DW, Ganesan S, Kass EM, Drapkin R, Grossman S, Wahrer DC, Sgroi DC, Lane WS, Haber DA, Livingston DM. BACH1, a novel helicase-like protein, interacts directly with BRCA1 and contributes to its DNA repair function. Cell. 2001 Apr 6;105(1):149-60. PMID:11301010
  2. ↑ Cantor S, Drapkin R, Zhang F, Lin Y, Han J, Pamidi S, Livingston DM. The BRCA1-associated protein BACH1 is a DNA helicase targeted by clinically relevant inactivating mutations. Proc Natl Acad Sci U S A. 2004 Feb 24;101(8):2357-62. PMID:14983014
  3. ↑ Litman R, Peng M, Jin Z, Zhang F, Zhang J, Powell S, Andreassen PR, Cantor SB. BACH1 is critical for homologous recombination and appears to be the Fanconi anemia gene product FANCJ. Cancer Cell. 2005 Sep;8(3):255-65. PMID:16153896 doi:S1535-6108(05)00262-X
  4. ↑ Bridge WL, Vandenberg CJ, Franklin RJ, Hiom K. The BRIP1 helicase functions independently of BRCA1 in the Fanconi anemia pathway for DNA crosslink repair. Nat Genet. 2005 Sep;37(9):953-7. Epub 2005 Aug 21. PMID:16116421 doi:10.1038/ng1627
  5. ↑ Litman R, Peng M, Jin Z, Zhang F, Zhang J, Powell S, Andreassen PR, Cantor SB. BACH1 is critical for homologous recombination and appears to be the Fanconi anemia gene product FANCJ. Cancer Cell. 2005 Sep;8(3):255-65. PMID:16153896 doi:S1535-6108(05)00262-X
  6. ↑ Bridge WL, Vandenberg CJ, Franklin RJ, Hiom K. The BRIP1 helicase functions independently of BRCA1 in the Fanconi anemia pathway for DNA crosslink repair. Nat Genet. 2005 Sep;37(9):953-7. Epub 2005 Aug 21. PMID:16116421 doi:10.1038/ng1627
  7. ↑ Wu Y, Sommers JA, Suhasini AN, Leonard T, Deakyne JS, Mazin AV, Shin-Ya K, Kitao H, Brosh RM Jr. Fanconi anemia group J mutation abolishes its DNA repair function by uncoupling DNA translocation from helicase activity or disruption of protein-DNA complexes. Blood. 2010 Nov 11;116(19):3780-91. doi: 10.1182/blood-2009-11-256016. Epub 2010 , Jul 16. PMID:20639400 doi:10.1182/blood-2009-11-256016
  8. ↑ Levran O, Attwooll C, Henry RT, Milton KL, Neveling K, Rio P, Batish SD, Kalb R, Velleuer E, Barral S, Ott J, Petrini J, Schindler D, Hanenberg H, Auerbach AD. The BRCA1-interacting helicase BRIP1 is deficient in Fanconi anemia. Nat Genet. 2005 Sep;37(9):931-3. Epub 2005 Aug 21. PMID:16116424 doi:10.1038/ng1624
  9. ↑ Levitus M, Waisfisz Q, Godthelp BC, de Vries Y, Hussain S, Wiegant WW, Elghalbzouri-Maghrani E, Steltenpool J, Rooimans MA, Pals G, Arwert F, Mathew CG, Zdzienicka MZ, Hiom K, De Winter JP, Joenje H. The DNA helicase BRIP1 is defective in Fanconi anemia complementation group J. Nat Genet. 2005 Sep;37(9):934-5. Epub 2005 Aug 21. PMID:16116423 doi:ng1625
  10. ↑ Yamane K, Tsuruo T. Conserved BRCT regions of TopBP1 and of the tumor suppressor BRCA1 bind strand breaks and termini of DNA. Oncogene. 1999 Sep 16;18(37):5194-203. PMID:10498869 doi:10.1038/sj.onc.1202922
  11. ↑ Makiniemi M, Hillukkala T, Tuusa J, Reini K, Vaara M, Huang D, Pospiech H, Majuri I, Westerling T, Makela TP, Syvaoja JE. BRCT domain-containing protein TopBP1 functions in DNA replication and damage response. J Biol Chem. 2001 Aug 10;276(32):30399-406. Epub 2001 Jun 6. PMID:11395493 doi:10.1074/jbc.M102245200
  12. ↑ Honda Y, Tojo M, Matsuzaki K, Anan T, Matsumoto M, Ando M, Saya H, Nakao M. Cooperation of HECT-domain ubiquitin ligase hHYD and DNA topoisomerase II-binding protein for DNA damage response. J Biol Chem. 2002 Feb 1;277(5):3599-605. Epub 2001 Nov 19. PMID:11714696 doi:10.1074/jbc.M104347200
  13. ↑ Liu K, Lin FT, Ruppert JM, Lin WC. Regulation of E2F1 by BRCT domain-containing protein TopBP1. Mol Cell Biol. 2003 May;23(9):3287-304. PMID:12697828
  14. ↑ Liu K, Luo Y, Lin FT, Lin WC. TopBP1 recruits Brg1/Brm to repress E2F1-induced apoptosis, a novel pRb-independent and E2F1-specific control for cell survival. Genes Dev. 2004 Mar 15;18(6):673-86. PMID:15075294 doi:10.1101/gad.1180204
  15. ↑ Kumagai A, Lee J, Yoo HY, Dunphy WG. TopBP1 activates the ATR-ATRIP complex. Cell. 2006 Mar 10;124(5):943-55. PMID:16530042 doi:10.1016/j.cell.2005.12.041
  16. ↑ Cantor SB, Bell DW, Ganesan S, Kass EM, Drapkin R, Grossman S, Wahrer DC, Sgroi DC, Lane WS, Haber DA, Livingston DM. BACH1, a novel helicase-like protein, interacts directly with BRCA1 and contributes to its DNA repair function. Cell. 2001 Apr 6;105(1):149-60. PMID:11301010
  17. ↑ Cantor S, Drapkin R, Zhang F, Lin Y, Han J, Pamidi S, Livingston DM. The BRCA1-associated protein BACH1 is a DNA helicase targeted by clinically relevant inactivating mutations. Proc Natl Acad Sci U S A. 2004 Feb 24;101(8):2357-62. PMID:14983014
  18. ↑ Litman R, Peng M, Jin Z, Zhang F, Zhang J, Powell S, Andreassen PR, Cantor SB. BACH1 is critical for homologous recombination and appears to be the Fanconi anemia gene product FANCJ. Cancer Cell. 2005 Sep;8(3):255-65. PMID:16153896 doi:S1535-6108(05)00262-X
  19. ↑ Bridge WL, Vandenberg CJ, Franklin RJ, Hiom K. The BRIP1 helicase functions independently of BRCA1 in the Fanconi anemia pathway for DNA crosslink repair. Nat Genet. 2005 Sep;37(9):953-7. Epub 2005 Aug 21. PMID:16116421 doi:10.1038/ng1627
  20. ↑ Leung CC, Gong Z, Chen J, Glover JN. Molecular basis of BACH1/FANCJ recognition by TopBP1 in DNA replication checkpoint control. J Biol Chem. 2011 Feb 11;286(6):4292-301. Epub 2010 Dec 2. PMID:21127055 doi:10.1074/jbc.M110.189555

3al3, resolution 2.15Å

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