PDBsum entry 1t15

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Antitumor protein PDB id
Protein chain
211 a.a. *
Waters ×156
* Residue conservation analysis
PDB id:
Name: Antitumor protein
Title: Crystal structure of the brca1 brct domains in complex with the phosphorylated interacting region from bach1 helicase
Structure: Breast cancer type 1 susceptibility protein. Chain: a. Fragment: bcrt 1, bcrt 2. Engineered: yes. Brca1 interacting protein c-terminal helicase 1. Chain: b. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: brca1. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693. Synthetic: yes
Biol. unit: Dimer (from PQS)
1.85Å     R-factor:   0.206     R-free:   0.222
Authors: J.A.Clapperton,I.A.Manke,D.M.Lowery,T.Ho,L.F.Haire, M.B.Yaffe,S.J.Smerdon
Key ref:
J.A.Clapperton et al. (2004). Structure and mechanism of BRCA1 BRCT domain recognition of phosphorylated BACH1 with implications for cancer. Nat Struct Mol Biol, 11, 512-518. PubMed id: 15133502 DOI: 10.1038/nsmb775
15-Apr-04     Release date:   11-May-04    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P38398  (BRCA1_HUMAN) -  Breast cancer type 1 susceptibility protein
1863 a.a.
211 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     nucleus   1 term 
  Biological process     DNA repair   1 term 
  Biochemical function     DNA binding     3 terms  


DOI no: 10.1038/nsmb775 Nat Struct Mol Biol 11:512-518 (2004)
PubMed id: 15133502  
Structure and mechanism of BRCA1 BRCT domain recognition of phosphorylated BACH1 with implications for cancer.
J.A.Clapperton, I.A.Manke, D.M.Lowery, T.Ho, L.F.Haire, M.B.Yaffe, S.J.Smerdon.
Germline mutations in the BRCA1 tumor suppressor gene often result in a significant increase in susceptibility to breast and ovarian cancers. Although the molecular basis of their effects remains largely obscure, many mutations are known to target the highly conserved C-terminal BRCT repeats that function as a phosphoserine/phosphothreonine-binding module. We report the X-ray crystal structure at a resolution of 1.85 A of the BRCA1 tandem BRCT domains in complex with a phosphorylated peptide representing the minimal interacting region of the DEAH-box helicase BACH1. The structure reveals the determinants of this novel class of BRCA1 binding events. We show that a subset of disease-linked mutations act through specific disruption of phospho-dependent BRCA1 interactions rather than through gross structural perturbation of the tandem BRCT domains.
  Selected figure(s)  
Figure 3.
Figure 3. Functional effects of tandem BRCT domain mutations. (a) Schematic representation of protein-peptide contacts between tandem BRCT domains and the BACH1 phosphopeptide. Dashed lines, hydrogen bonds; pink crescents, van der Waals interactions; green circles, water molecules. (b) The wild-type and mutant myc-tagged tandem BRCT domain constructs containing the indicated mutations were analyzed for binding to a bead-immobilized optimal tandem BRCT domain-interacting phosphopeptide, YDIpSQVFPF, or its nonphosphorylated counterpart. The weak phospho-independent binding of the R1699Q mutant was observed using ten-fold more sample input than was used in the other lanes. (c) U2OS cells transfected with wild-type and mutant myc-tagged tandem BRCT domain constructs were analyzed for association with endogenous BACH1.
Figure 4.
Figure 4. The Phe(+3) position of the BACH1 phosphopeptide is essential for tandem BRCT domain binding specificity. (a) Phe1704, Met1775 and Leu1704 from tandem BRCT domains form a hydrophobic pocket to accommodate the Phe(+3) position of the BACH1 phosphopeptide. (b) Superposition of the crystal structure of the M1775R tandem BRCT domain mutant18 with the wild-type BACH1 -phosphopeptide complex reveals that this mutation occludes the BACH1 Phe(+3) position. (c) Wild-type (WT) tandem BRCT domains and the M1775R mutant binding to a BACH1 phosphopeptide spot array. The M1775R mutant spot blot was carried out using ten times the amount of protein and was exposed to film for a substantially longer amount of time than the wild-type protein.
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Mol Biol (2004, 11, 512-518) copyright 2004.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20724438 M.Rappas, A.W.Oliver, and L.H.Pearl (2011).
Structure and function of the Rad9-binding region of the DNA-damage checkpoint adaptor TopBP1.
  Nucleic Acids Res, 39, 313-324.
PDB codes: 2xnh 2xnk
20681793 A.C.Nelson, and J.T.Holt (2010).
Impact of RING and BRCT domain mutations on BRCA1 protein stability, localization and recruitment to DNA damage.
  Radiat Res, 174, 1.  
20455026 A.Y.Steffensen, L.Jønson, B.Ejlertsen, A.M.Gerdes, F.C.Nielsen, and T.V.Hansen (2010).
Identification of a Danish breast/ovarian cancer family double heterozygote for BRCA1 and BRCA2 mutations.
  Fam Cancer, 9, 283-287.  
  19937654 C.C.Leung, E.Kellogg, A.Kuhnert, F.Hänel, D.Baker, and J.N.Glover (2010).
Insights from the crystal structure of the sixth BRCT domain of topoisomerase IIbeta binding protein 1.
  Protein Sci, 19, 162-167.
PDB code: 3jve
20164689 C.G.Murphy, and M.E.Moynahan (2010).
BRCA gene structure and function in tumor suppression: a repair-centric perspective.
  Cancer J, 16, 39-47.  
20177395 M.E.Moynahan, and M.Jasin (2010).
Mitotic homologous recombination maintains genomic stability and suppresses tumorigenesis.
  Nat Rev Mol Cell Biol, 11, 196-207.  
19925808 M.W.Richards, J.W.Leung, S.M.Roe, K.Li, J.Chen, and R.Bayliss (2010).
A pocket on the surface of the N-terminal BRCT domain of Mcph1 is required to prevent abnormal chromosome condensation.
  J Mol Biol, 395, 908-915.
PDB code: 2wt8
20122900 P.R.Joseph, Z.Yuan, E.A.Kumar, G.L.Lokesh, S.Kizhake, K.Rajarathnam, and A.Natarajan (2010).
Structural characterization of BRCT-tetrapeptide binding interactions.
  Biochem Biophys Res Commun, 393, 207-210.  
20159462 S.J.Campbell, R.A.Edwards, and J.N.Glover (2010).
Comparison of the structures and peptide binding specificities of the BRCT domains of MDC1 and BRCA1.
  Structure, 18, 167-176.
PDB codes: 3k05 3k0h 3k0k 3k15 3k16
19706752 A.De Nicolo, E.Parisini, Q.Zhong, M.Dalla Palma, K.A.Stoeckert, S.M.Domchek, K.L.Nathanson, M.A.Caligo, M.Vidal, M.E.Cusick, and J.E.Garber (2009).
Multimodal assessment of protein functional deficiency supports pathogenicity of BRCA1 p.V1688del.
  Cancer Res, 69, 7030-7037.  
19200354 E.B.Gomez Garcia, J.C.Oosterwijk, M.Timmermans, C.J.van Asperen, F.B.Hogervorst, N.Hoogerbrugge, R.Oldenburg, S.Verhoef, C.J.Dommering, M.G.Ausems, T.A.van Os, A.H.van der Hout, M.Ligtenberg, A.van den Ouweland, R.B.van der Luijt, J.T.Wijnen, J.J.Gille, P.J.Lindsey, P.Devilee, M.J.Blok, and M.P.Vreeswijk (2009).
A method to assess the clinical significance of unclassified variants (UVs) in the BRCA1 and BRCA2 genes based on cancer family history.
  Breast Cancer Res, 11, R8.  
19452558 I.Drikos, G.Nounesis, and C.E.Vorgias (2009).
Characterization of cancer-linked BRCA1-BRCT missense variants and their interaction with phosphoprotein targets.
  Proteins, 77, 464-476.  
19804755 R.S.Williams, G.E.Dodson, O.Limbo, Y.Yamada, J.S.Williams, G.Guenther, S.Classen, J.N.Glover, H.Iwasaki, P.Russell, and J.A.Tainer (2009).
Nbs1 flexibly tethers Ctp1 and Mre11-Rad50 to coordinate DNA double-strand break processing and repair.
  Cell, 139, 87-99.
PDB codes: 3hue 3huf
19187758 T.Usui, S.S.Foster, and J.H.Petrini (2009).
Maintenance of the DNA-damage checkpoint requires DNA-damage-induced mediator protein oligomerization.
  Mol Cell, 33, 147-159.  
18628483 A.De Nicolo, M.Tancredi, G.Lombardi, C.C.Flemma, S.Barbuti, C.Di Cristofano, B.Sobhian, G.Bevilacqua, R.Drapkin, and M.A.Caligo (2008).
A novel breast cancer-associated BRIP1 (FANCJ/BACH1) germ-line mutation impairs protein stability and function.
  Clin Cancer Res, 14, 4672-4680.  
19026779 A.Ghosh, S.Shuman, and C.D.Lima (2008).
The structure of Fcp1, an essential RNA polymerase II CTD phosphatase.
  Mol Cell, 32, 478-490.
PDB codes: 3ef0 3ef1
18772227 A.Kinner, W.Wu, C.Staudt, and G.Iliakis (2008).
Gamma-H2AX in recognition and signaling of DNA double-strand breaks in the context of chromatin.
  Nucleic Acids Res, 36, 5678-5694.  
18579587 A.Kumar, W.S.Joo, G.Meinke, S.Moine, E.N.Naumova, and P.A.Bullock (2008).
Evidence for a structural relationship between BRCT domains and the helicase domains of the replication initiators encoded by the Polyomaviridae and Papillomaviridae families of DNA tumor viruses.
  J Virol, 82, 8849-8862.  
18582474 C.Xu, L.Wu, G.Cui, M.V.Botuyan, J.Chen, and G.Mer (2008).
Structure of a second BRCT domain identified in the nijmegen breakage syndrome protein Nbs1 and its function in an MDC1-dependent localization of Nbs1 to DNA damage sites.
  J Mol Biol, 381, 361-372.
PDB code: 2k2w
18951449 F.J.Couch, L.J.Rasmussen, R.Hofstra, A.N.Monteiro, M.S.Greenblatt, Wind, P.Boffetta, F.Couch, Wind, D.Easton, D.Eccles, W.Foulkes, M.Genuardi, D.Goldgar, M.Greenblatt, R.Hofstra, F.Hogervorst, N.Hoogerbrugge, S.Plon, P.Radice, L.Rasmussen, O.Sinilnikova, A.Spurdle, and S.V.Tavtigian (2008).
Assessment of functional effects of unclassified genetic variants.
  Hum Mutat, 29, 1314-1326.  
17620310 J.Brunet, A.Vazquez-Martin, R.Colomer, B.Graña-Suarez, B.Martin-Castillo, and J.A.Menendez (2008).
BRCA1 and acetyl-CoA carboxylase: the metabolic syndrome of breast cancer.
  Mol Carcinog, 47, 157-163.  
18448671 L.Tang, A.Sahasranaman, J.Jakovljevic, E.Schleifman, and J.L.Woolford (2008).
Interactions among Ytm1, Erb1, and Nop7 required for assembly of the Nop7-subcomplex in yeast preribosomes.
  Mol Biol Cell, 19, 2844-2856.  
18619997 M.S.Cortese, V.N.Uversky, and A.K.Dunker (2008).
Intrinsic disorder in scaffold proteins: getting more from less.
  Prog Biophys Mol Biol, 98, 85.  
18285836 M.Tischkowitz, N.Hamel, M.A.Carvalho, G.Birrane, A.Soni, E.H.van Beers, S.A.Joosse, N.Wong, D.Novak, L.A.Quenneville, S.A.Grist, P.M.Nederlof, D.E.Goldgar, S.V.Tavtigian, A.N.Monteiro, J.A.Ladias, and W.D.Foulkes (2008).
Pathogenicity of the BRCA1 missense variant M1775K is determined by the disruption of the BRCT phosphopeptide-binding pocket: a multi-modal approach.
  Eur J Hum Genet, 16, 820-832.
PDB code: 2ing
18842000 R.A.Edwards, M.S.Lee, S.E.Tsutakawa, R.S.Williams, J.A.Tainer, and J.N.Glover (2008).
The BARD1 C-terminal domain structure and interactions with polyadenylation factor CstF-50.
  Biochemistry, 47, 11446-11456.  
18717574 Y.Nominé, M.V.Botuyan, Z.Bajzer, W.G.Owen, A.J.Caride, E.Wasielewski, and G.Mer (2008).
Kinetic analysis of interaction of BRCA1 tandem breast cancer c-terminal domains with phosphorylated peptides reveals two binding conformations.
  Biochemistry, 47, 9866-9879.  
18452305 Y.Shen, and L.Tong (2008).
Structural evidence for direct interactions between the BRCT domains of human BRCA1 and a phospho-peptide from human ACC1.
  Biochemistry, 47, 5767-5773.
PDB code: 3coj
17063491 C.A.Gough, T.Gojobori, and T.Imanishi (2007).
Cancer-related mutations in BRCA1-BRCT cause long-range structural changes in protein-protein binding sites: a molecular dynamics study.
  Proteins, 66, 69-86.  
17915942 E.F.DeRose, M.W.Clarkson, S.A.Gilmore, C.J.Galban, A.Tripathy, J.M.Havener, G.A.Mueller, D.A.Ramsden, R.E.London, and A.L.Lee (2007).
Solution structure of polymerase mu's BRCT Domain reveals an element essential for its role in nonhomologous end joining.
  Biochemistry, 46, 12100-12110.
PDB code: 2htf
17690115 I.M.Munoz, P.A.Jowsey, R.Toth, and J.Rouse (2007).
Phospho-epitope binding by the BRCT domains of hPTIP controls multiple aspects of the cellular response to DNA damage.
  Nucleic Acids Res, 35, 5312-5322.  
17308087 M.A.Carvalho, S.M.Marsillac, R.Karchin, S.Manoukian, S.Grist, R.F.Swaby, T.P.Urmenyi, E.Rondinelli, R.Silva, L.Gayol, L.Baumbach, R.Sutphen, J.L.Pickard-Brzosowicz, K.L.Nathanson, A.Sali, D.Goldgar, F.J.Couch, P.Radice, and A.N.Monteiro (2007).
Determination of cancer risk associated with germ line BRCA1 missense variants by functional analysis.
  Cancer Res, 67, 1494-1501.  
17848578 M.Laufer, S.V.Nandula, A.P.Modi, S.Wang, M.Jasin, V.V.Murty, T.Ludwig, and R.Baer (2007).
Structural requirements for the BARD1 tumor suppressor in chromosomal stability and homology-directed DNA repair.
  J Biol Chem, 282, 34325-34333.  
17561994 P.Vasickova, E.Machackova, M.Lukesova, J.Damborsky, O.Horky, H.Pavlu, J.Kuklova, V.Kosinova, M.Navratilova, and L.Foretova (2007).
High occurrence of BRCA1 intragenic rearrangements in hereditary breast and ovarian cancer syndrome in the Czech Republic.
  BMC Med Genet, 8, 32.  
17596542 R.Gupta, S.Sharma, J.A.Sommers, M.K.Kenny, S.B.Cantor, and R.M.Brosh (2007).
FANCJ (BACH1) helicase forms DNA damage inducible foci with replication protein A and interacts physically and functionally with the single-stranded DNA-binding protein.
  Blood, 110, 2390-2398.  
16854521 R.Ralhan, J.Kaur, R.Kreienberg, and L.Wiesmüller (2007).
Links between DNA double strand break repair and breast cancer: accumulating evidence from both familial and nonfamilial cases.
  Cancer Lett, 248, 1.  
17984965 S.D.Taverna, H.Li, A.J.Ruthenburg, C.D.Allis, and D.J.Patel (2007).
How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers.
  Nat Struct Mol Biol, 14, 1025-1040.  
17317137 T.Pawson (2007).
Dynamic control of signaling by modular adaptor proteins.
  Curr Opin Cell Biol, 19, 112-116.  
17643121 Z.Liu, J.Wu, and X.Yu (2007).
CCDC98 targets BRCA1 to DNA damage sites.
  Nat Struct Mol Biol, 14, 716-720.  
16829979 B.T.Seet, I.Dikic, M.M.Zhou, and T.Pawson (2006).
Reading protein modifications with interaction domains.
  Nat Rev Mol Cell Biol, 7, 473-483.  
17094803 D.C.Zappulla, A.S.Maharaj, J.J.Connelly, R.A.Jockusch, and R.Sternglanz (2006).
Rtt107/Esc4 binds silent chromatin and DNA repair proteins using different BRCT motifs.
  BMC Mol Biol, 7, 40.  
17161371 J.Liu, Y.Pan, B.Ma, and R.Nussinov (2006).
"Similarity trap" in protein-protein interactions could be carcinogenic: simulations of p53 core domain complexed with 53BP1 and BRCA1 BRCT domains.
  Structure, 14, 1811-1821.  
16528612 J.N.Glover (2006).
Insights into the molecular basis of human hereditary breast cancer from studies of the BRCA1 BRCT domain.
  Fam Cancer, 5, 89-93.  
16889898 M.F.Moran, J.Tong, P.Taylor, and R.M.Ewing (2006).
Emerging applications for phospho-proteomics in cancer molecular therapeutics.
  Biochim Biophys Acta, 1766, 230-241.  
16361700 M.Kobayashi, F.Figaroa, N.Meeuwenoord, L.E.Jansen, and G.Siegal (2006).
Characterization of the DNA binding and structural properties of the BRCT region of human replication factor C p140 subunit.
  J Biol Chem, 281, 4308-4317.  
16462773 M.Peng, R.Litman, Z.Jin, G.Fong, and S.B.Cantor (2006).
BACH1 is a DNA repair protein supporting BRCA1 damage response.
  Oncogene, 25, 2245-2253.  
15923272 P.K.Lovelock, S.Healey, W.Au, E.Y.Sum, A.Tesoriero, E.M.Wong, S.Hinson, R.Brinkworth, A.Bekessy, O.Diez, L.Izatt, E.Solomon, M.Jenkins, H.Renard, J.Hopper, P.Waring, S.V.Tavtigian, D.Goldgar, G.J.Lindeman, J.E.Visvader, F.J.Couch, B.R.Henderson, M.Southey, G.Chenevix-Trench, A.B.Spurdle, and M.A.Brown (2006).
Genetic, functional, and histopathological evaluation of two C-terminal BRCA1 missense variants.
  J Med Genet, 43, 74-83.  
17145708 R.Gupta, S.Sharma, K.M.Doherty, J.A.Sommers, S.B.Cantor, and R.M.Brosh (2006).
Inhibition of BACH1 (FANCJ) helicase by backbone discontinuity is overcome by increased motor ATPase or length of loading strand.
  Nucleic Acids Res, 34, 6673-6683.  
15576564 B.A.Joughin, B.Tidor, and M.B.Yaffe (2005).
A computational method for the analysis and prediction of protein:phosphopeptide-binding sites.
  Protein Sci, 14, 131-139.  
15629715 I.A.Manke, A.Nguyen, D.Lim, M.Q.Stewart, A.E.Elia, and M.B.Yaffe (2005).
MAPKAP kinase-2 is a cell cycle checkpoint kinase that regulates the G2/M transition and S phase progression in response to UV irradiation.
  Mol Cell, 17, 37-48.  
16049003 M.S.Lee, R.A.Edwards, G.L.Thede, and J.N.Glover (2005).
Structure of the BRCT repeat domain of MDC1 and its specificity for the free COOH-terminal end of the gamma-H2AX histone tail.
  J Biol Chem, 280, 32053-32056.
PDB code: 2ado
16377563 M.Stucki, J.A.Clapperton, D.Mohammad, M.B.Yaffe, S.J.Smerdon, and S.P.Jackson (2005).
MDC1 directly binds phosphorylated histone H2AX to regulate cellular responses to DNA double-strand breaks.
  Cell, 123, 1213-1226.
PDB code: 2azm
15878853 R.Gupta, S.Sharma, J.A.Sommers, Z.Jin, S.B.Cantor, and R.M.Brosh (2005).
Analysis of the DNA substrate specificity of the human BACH1 helicase associated with breast cancer.
  J Biol Chem, 280, 25450-25460.  
16333323 R.S.Williams, N.Bernstein, M.S.Lee, M.L.Rakovszky, D.Cui, R.Green, M.Weinfeld, and J.N.Glover (2005).
Structural basis for phosphorylation-dependent signaling in the DNA-damage response.
  Biochem Cell Biol, 83, 721-727.  
16116421 W.L.Bridge, C.J.Vandenberg, R.J.Franklin, and K.Hiom (2005).
The BRIP1 helicase functions independently of BRCA1 in the Fanconi anemia pathway for DNA crosslink repair.
  Nat Genet, 37, 953-957.  
15569676 W.W.Au, and B.R.Henderson (2005).
The BRCA1 RING and BRCT domains cooperate in targeting BRCA1 to ionizing radiation-induced nuclear foci.
  J Biol Chem, 280, 6993-7001.  
15341721 G.Charier, J.Couprie, B.Alpha-Bazin, V.Meyer, E.Quéméneur, R.Guérois, I.Callebaut, B.Gilquin, and S.Zinn-Justin (2004).
The Tudor tandem of 53BP1: a new structural motif involved in DNA and RG-rich peptide binding.
  Structure, 12, 1551-1562.
PDB code: 1ssf
15501676 J.N.Glover, R.S.Williams, and M.S.Lee (2004).
Interactions between BRCT repeats and phosphoproteins: tangled up in two.
  Trends Biochem Sci, 29, 579-585.  
15133503 R.S.Williams, M.S.Lee, D.D.Hau, and J.N.Glover (2004).
Structural basis of phosphopeptide recognition by the BRCT domain of BRCA1.
  Nat Struct Mol Biol, 11, 519-525.
PDB codes: 1t2u 1t2v
15485915 X.Yu, and J.Chen (2004).
DNA damage-induced cell cycle checkpoint control requires CtIP, a phosphorylation-dependent binding partner of BRCA1 C-terminal domains.
  Mol Cell Biol, 24, 9478-9486.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.