PDBsum entry: 1t29

Signaling protein

PDB id: 1t29

Contents

Protein chains

211 a.a. *

12 a.a. *

Waters ×235

* Residue conservation analysis

PDB id:

1t29

Name:

Signaling protein

Title:

Crystal structure of the brca1 brct repeats bound to a phosphorylated bach1 peptide

Structure:

Breast cancer type 1 susceptibility protein. Chain: a. Fragment: brct repeats of brca1 (residues 1646-1859). Engineered: yes. Bach1 phosphorylated peptide. Chain: b. Fragment: residues 985-998. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Synthetic: yes. Other_details: the peptide was chemically synthesized. The sequence of the peptide occurs naturally in humans

Biol. unit:

Dimer (from PQS)

Resolution:

2.30Å R-factor: 0.252 R-free: 0.266

Authors:

E.N.Shiozaki,L.Gu,N.Yan,Y.Shi

Key ref:

E.N.Shiozaki et al. (2004). Structure of the BRCT repeats of BRCA1 bound to a BACH1 phosphopeptide: implications for signaling. Mol Cell, 14, 405-412. PubMed id: 15125843 DOI: 10.1016/S1097-2765(04)00238-2

Date:

20-Apr-04 Release date: 11-May-04

Protein chain

P38398  (BRCA1_HUMAN) -  Breast cancer type 1 susceptibility protein

Seq: 1863 a.a.

Struc: 211 a.a.

Protein chain

No UniProt id for this chain

 Gene Ontology (GO) functional annotation 

• Cellular component: intracellular (2 terms)
• Biological process: DNA repair (1 term)
• Biochemical function: DNA binding (2 terms)

DOI no: 10.1016/S1097-2765(04)00238-2

Mol Cell 14:405-412 (2004)

PubMed id: 15125843

Structure of the BRCT repeats of BRCA1 bound to a BACH1 phosphopeptide: implications for signaling.

E.N.Shiozaki, L.Gu, N.Yan, Y.Shi.

ABSTRACT

The recognition of the phosphorylated BACH1 helicase by the BRCA1 C-terminal (BRCT) repeats is important to the tumor suppressor function of BRCA1. Here we report the crystal structure of the BRCT repeats of human BRCA1 bound to a phosphorylated BACH1 peptide at 2.3 A resolution. The phosphorylated serine 990 and phenylalanine 993 of BACH1 anchor the binding to BRCA1 through specific interactions with a surface cleft at the junction of the two BRCT repeats. This surface cleft is highly conserved in BRCA1 across species, suggesting an evolutionarily conserved function of phosphopeptide recognition. Importantly, conserved amino acids critical for BACH1 binding are frequently targeted for missense mutations in breast cancer. These mutations greatly diminish the ability of BRCA1 to interact with the phosphorylated BACH1 peptide. Additional structural analysis revealed significant implications for understanding the function of the BRCT family of proteins in DNA damage and repair signaling.

Selected figure(s)

Figure 2.
Figure 2. Specific Recognition of the Phosphorylated BACH1 Peptide by the BRCT Repeats of BRCA1(A) Stereo view of the BRCT-BACH1 interface. The two tandem BRCT repeats are colored blue and green. The bound BACH1 peptide is shown in magenta. Hydrogen bonds are represented by red dashed lines. Oxygen and nitrogen atoms are shown as red and blue balls, respectively.(B) Sequence alignment of BRCA1 orthologs from human, mouse, chicken, and fish. Color choices for the two BRCT motifs are the same as in Figure 1A. Conserved residues are highlighted in yellow. Hydrogen bonds to the side chains and backbone groups are indicated below the sequences by red and green triangles, respectively; van der Waals contacts are shown by blue squares. Residues that were targeted for missense mutations in at least five breast cancer patients are identified by red columns above the sequences, with the height of the column corresponding to the number of mutations.

Figure 3.
Figure 3. The BRCT-BACH1 Interaction Is Frequently Targeted for Inactivation in Breast Cancers(A) The conserved surface cleft of the BRCT repeats is most frequently targeted for mutations. Cancer-derived missense mutations in the BRCT repeats of BRCA1 were mapped onto the surface of the structure, with different frequencies encoded by distinct colors. Two of the most prevalent mutations, Met1775Arg and Arg1699Ala, affect residues in the surface cleft that make critical interactions to the phosphorylated BACH1 peptide.(B) Tumor-derived mutations in BRCA1 result in significantly weakened interactions with the phosphorylated BACH1 peptide. Representative ITC results are shown between the phosphorylated BACH1 peptide and the BRCT repeats of BRCA1.

The above figures are reprinted by permission from Cell Press: Mol Cell (2004, 14, 405-412) copyright 2004.

Figures were selected by an automated process.