Structure of the 53BP1 BRCT region bound to p53 and its comparison to the Brca1 BRCT structure

Genes Dev. 2002 Mar 1;16(5):583-93. doi: 10.1101/gad.959202.

Abstract

Brca1 C-terminal (BRCT) domains are a common protein-protein interaction motif in proteins involved in the DNA damage response and DNA repair. The DNA-damage response protein 53BP1 has two BRCT domains that bind to the DNA-binding domain of p53. The 53BP1 tandem-BRCT region is homologous to the tandem-BRCT region of Brca1, which is involved in double-strand break repair and homologous recombination and which binds BACH1, a member of the DEAH helicase family. Here we report the structures of a human 53BP1-p53 complex and of the rat Brca1 BRCT repeats. The 53BP1-p53 structure shows that the two BRCT repeats are arranged tandemly and pack extensively through an interface that also involves the inter-repeat linker. The first BRCT repeat and the linker together bind p53 on a region that overlaps with the DNA-binding surface of p53 and involves p53 residues that are mutated in cancer and are important for DNA binding. Comparison with the structure of the tandem-BRCT region of Brca1 shows a remarkable conservation of the repeat arrangement and of the inter-BRCT repeat interface. Analysis of human BRCA1 tumor-derived mutations and conservation identifies a potential protein-binding site that we show through mutagenesis is involved in BACH1 binding. The BACH1-binding region of Brca1 consists of a unique insertion in the first BRCT repeat and the inter-repeat linker and is analogous to the region of 53BP1 that binds p53.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • BRCA1 Protein / chemistry*
  • Carrier Proteins / chemistry*
  • Humans
  • Intracellular Signaling Peptides and Proteins*
  • Models, Molecular
  • Molecular Sequence Data
  • Phosphoproteins*
  • Rats
  • Sequence Homology, Amino Acid
  • Tumor Suppressor Protein p53 / chemistry*
  • Tumor Suppressor p53-Binding Protein 1

Substances

  • BRCA1 Protein
  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • Phosphoproteins
  • TP53BP1 protein, human
  • Tumor Suppressor Protein p53
  • Tumor Suppressor p53-Binding Protein 1

Associated data

  • PDB/1KZY
  • PDB/1L0B