PDBsum entry 2ing

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DNA binding protein PDB id
Protein chain
208 a.a. *
SO4 ×2
* Residue conservation analysis
PDB id:
Name: DNA binding protein
Title: X-ray structure of the brca1 brct mutant m1775k
Structure: Breast cancer type 1 susceptibility protein. Chain: x. Fragment: brct1, brct2. Synonym: ring finger protein 53. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: brca1, rnf53. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693.
3.60Å     R-factor:   0.251     R-free:   0.302
Authors: G.Birrane,A.Soni,J.A.A.Ladias
Key ref: M.Tischkowitz et al. (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. PubMed id: 18285836
07-Oct-06     Release date:   04-Sep-07    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P38398  (BRCA1_HUMAN) -  Breast cancer type 1 susceptibility protein
1863 a.a.
208 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     nucleus   1 term 
  Biological process     DNA repair   1 term 
  Biochemical function     DNA binding     3 terms  


Eur J Hum Genet 16:820-832 (2008)
PubMed id: 18285836  
Pathogenicity of the BRCA1 missense variant M1775K is determined by the disruption of the BRCT phosphopeptide-binding pocket: a multi-modal approach.
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, W.D.Foulkes.
A number of germ-line mutations in the BRCA1 gene confer susceptibility to breast and ovarian cancer. However, it remains difficult to determine whether many single amino-acid (missense) changes in the BRCA1 protein that are frequently detected in the clinical setting are pathologic or not. Here, we used a combination of functional, crystallographic, biophysical, molecular and evolutionary techniques, and classical genetic segregation analysis to demonstrate that the BRCA1 missense variant M1775K is pathogenic. Functional assays in yeast and mammalian cells showed that the BRCA1 BRCT domains carrying the amino-acid change M1775K displayed markedly reduced transcriptional activity, indicating that this variant represents a deleterious mutation. Importantly, the M1775K mutation disrupted the phosphopeptide-binding pocket of the BRCA1 BRCT domains, thereby inhibiting the BRCA1 interaction with the proteins BRIP1 and CtIP, which are involved in DNA damage-induced checkpoint control. These results indicate that the integrity of the BRCT phosphopeptide-binding pocket is critical for the tumor suppression function of BRCA1. Moreover, this study demonstrates that multiple lines of evidence obtained from a combination of functional, structural, molecular and evolutionary techniques, and classical genetic segregation analysis are required to confirm the pathogenicity of rare variants of disease-susceptibility genes and obtain important insights into the underlying pathogenetic mechanisms.

Literature references that cite this PDB file's key reference

  PubMed id Reference
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.  
20608970 R.J.Linger, and P.A.Kruk (2010).
BRCA1 16 years later: risk-associated BRCA1 mutations and their functional implications.
  FEBS J, 277, 3086-3096.  
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.  
18704682 S.A.Joosse, E.H.van Beers, I.H.Tielen, H.Horlings, J.L.Peterse, N.Hoogerbrugge, M.J.Ligtenberg, L.F.Wessels, P.Axwijk, S.Verhoef, F.B.Hogervorst, and P.M.Nederlof (2009).
Prediction of BRCA1-association in hereditary non-BRCA1/2 breast carcinomas with array-CGH.
  Breast Cancer Res Treat, 116, 479-489.  
18951447 R.M.Hofstra, A.B.Spurdle, D.Eccles, W.D.Foulkes, Wind, N.Hoogerbrugge, F.B.Hogervorst, 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).
Tumor characteristics as an analytic tool for classifying genetic variants of uncertain clinical significance.
  Hum Mutat, 29, 1292-1303.  
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