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Antitumor protein PDB id
1n5o
Jmol
Contents
Protein chain
207 a.a. *
Ligands
SO4 ×2
Metals
_CO
Waters ×59
* Residue conservation analysis
PDB id:
1n5o
Name: Antitumor protein
Title: Structural consequences of a cancer-causing brca1-brct misse mutation
Structure: Breast cancer type 1 susceptibility protein. Chain: x. Fragment: brct (residues 1646-1859). Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: brca1. Expressed in: escherichia coli. Expression_system_taxid: 562
Resolution:
2.80Å     R-factor:   0.275     R-free:   0.298
Authors: R.S.Williams,J.N.M.Glover
Key ref:
R.S.Williams and J.N.Glover (2003). Structural consequences of a cancer-causing BRCA1-BRCT missense mutation. J Biol Chem, 278, 2630-2635. PubMed id: 12427738 DOI: 10.1074/jbc.M210019200
Date:
06-Nov-02     Release date:   25-Dec-02    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P38398  (BRCA1_HUMAN) -  Breast cancer type 1 susceptibility protein
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		1863 a.a.
207 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     intracellular   2 terms 
  Biological process     DNA repair   1 term 
  Biochemical function     DNA binding     2 terms  

 

 
DOI no: 10.1074/jbc.M210019200 J Biol Chem 278:2630-2635 (2003)
PubMed id: 12427738  
 
 
Structural consequences of a cancer-causing BRCA1-BRCT missense mutation.
R.S.Williams, J.N.Glover.
 
  ABSTRACT  
 
The integrity of the carboxyl-terminal BRCT repeat region is critical for BRCA1 tumor suppressor function; however, the molecular details of how a number of clinically derived BRCT missense mutations affect BRCA1 function remain largely unknown. Here we assess the structural response of the BRCT tandem repeat domain to a well characterized, cancer-associated single amino acid substitution, Met-1775 --> Arg-1775. The structure of BRCT-M1775R reveals that the mutated side chain is extruded from the protein hydrophobic core, thereby altering the protein surface. Charge-charge repulsion, rearrangement of the hydrophobic core, and disruption of the native hydrogen bonding network at the interface between the two BRCT repeats contribute to the conformational instability of BRCT-M1775R. Destabilization and global unfolding of the mutated BRCT domain at physiological temperatures explain the pleiotropic molecular and genetic defects associated with the BRCA1-M1775R protein.
 
  Selected figure(s)  
 
Figure 1.
Fig. 1. Evolutionary conservation of the Met-1775 packing environment. A, ribbons diagram of the BRCT repeat region of BRCA1. Met-1775 ( red) in BRCT-WT is positioned between the two BRCT fold repeats. Met-1775 (red surface) lies in a hydrophobic pocket created by Leu-1701, Phe-1704, Leu-1780, Met-1783 (behind Met-1775), Arg-1835, and Leu-1839 (gray surfaces). B, multiple sequence alignment of BRCA1 homologues for the BRCT regions surrounding Met-1775. Met-1775 is red, and contacting amino acids are blue. Numbering is for human BRCA1. 		Figure 5.
Fig. 5. Structural rearrangements accommodate M1775R. A, native hydrogen bonding interactions proximal to Met-1775. Hydrogen bonds are indicated by dashed lines. B, hydrogen bonding, salt bridging for mutant M1775R. Arg-1775 participates in the coordination of two solvent anions, S1 and S2, and has been flipped out from the hydrophobic pocket where Met-1775 normally packs. C, cutaway view of the hydrophobic core of the BRCT. Structural overlay of WT ( gray with red surface) and M1775R (gold with gray surface) hydrophobic core residues that move upon mutation. D, charge potential GRASP surface for BRCT-WT. Blue surface reflects positive charge potential, and red is negative. The arrow indicates a hydrophobic groove near Met-1775. E, charge potential GRASP surface for BRCT-M1775R. Green spheres mark the positions of bound anions.
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2003, 278, 2630-2635) copyright 2003.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20737206 L.Guidugli, C.Rugani, G.Lombardi, P.Aretini, A.Galli, and M.A.Caligo (2011).
A recombination-based method to characterize human BRCA1 missense variants.
  Breast Cancer Res Treat, 125, 265-272.  
20104584 A.Borg, R.W.Haile, K.E.Malone, M.Capanu, A.Diep, T.Törngren, S.Teraoka, C.B.Begg, D.C.Thomas, P.Concannon, L.Mellemkjaer, L.Bernstein, L.Tellhed, S.Xue, E.R.Olson, X.Liang, J.Dolle, A.L.Børresen-Dale, and J.L.Bernstein (2010).
Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study.
  Hum Mutat, 31, E1200-E1240.  
  21203981 J.Wu, L.Y.Lu, and X.Yu (2010).
The role of BRCA1 in DNA damage response.
  Protein Cell, 1, 117-123.  
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
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.  
18992264 M.Carvalho, M.A.Pino, R.Karchin, J.Beddor, M.Godinho-Netto, R.D.Mesquita, R.S.Rodarte, D.C.Vaz, V.A.Monteiro, S.Manoukian, M.Colombo, C.B.Ripamonti, R.Rosenquist, G.Suthers, A.Borg, P.Radice, S.A.Grist, A.N.Monteiro, and B.Billack (2009).
Analysis of a set of missense, frameshift, and in-frame deletion variants of BRCA1.
  Mutat Res, 660, 1.  
18951449 F.J.Couch, L.J.Rasmussen, R.Hofstra, A.N.Monteiro, M.S.Greenblatt, N.de Wind, P.Boffetta, F.Couch, N.de 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.  
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.  
18415037 T.C.Lee, A.S.Lee, and K.B.Li (2008).
Incorporating the amino acid properties to predict the significance of missense mutations.
  Amino Acids, 35, 615-626.  
18662409 W.De Silva, E.H.Karunanayake, K.H.Tennekoon, M.Allen, I.Amarasinghe, P.Angunawala, and M.H.Ziard (2008).
Novel sequence variants and a high frequency of recurrent polymorphisms in BRCA1 gene in Sri Lankan breast cancer patients and at risk individuals.
  BMC Cancer, 8, 214.  
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.  
18036263 P.K.Lovelock, A.B.Spurdle, M.T.Mok, D.J.Farrugia, S.R.Lakhani, S.Healey, S.Arnold, D.Buchanan, K.Investigators, F.J.Couch, B.R.Henderson, D.E.Goldgar, S.V.Tavtigian, G.Chenevix-Trench, and M.A.Brown (2007).
Identification of BRCA1 missense substitutions that confer partial functional activity: potential moderate risk variants?
  Breast Cancer Res, 9, R82.  
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.  
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.  
16998500 P.B.Mullan, J.E.Quinn, and D.P.Harkin (2006).
The role of BRCA1 in transcriptional regulation and cell cycle control.
  Oncogene, 25, 5854-5863.  
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.  
16047333 E.J.Majdak, J.Debniak, T.Milczek, C.J.Cornelisse, P.Devilee, J.Emerich, J.Jassem, and G.H.De Bock (2005).
Prognostic impact of BRCA1 pathogenic and BRCA1/BRCA2 unclassified variant mutations in patients with ovarian carcinoma.
  Cancer, 104, 1004-1012.  
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.  
15133502 J.A.Clapperton, I.A.Manke, D.M.Lowery, T.Ho, L.F.Haire, M.B.Yaffe, and S.J.Smerdon (2004).
Structure and mechanism of BRCA1 BRCT domain recognition of phosphorylated BACH1 with implications for cancer.
  Nat Struct Mol Biol, 11, 512-518.
PDB code: 1t15
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
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.