4Y2G

Structure of BRCA1 BRCT domains in complex with Abraxas single phosphorylated peptide

Summary for 4Y2G

• Entry DOI: 10.2210/pdb4y2g/pdb
• Descriptor: Breast cancer type 1 susceptibility protein, BRCA1-A complex subunit Abraxas (3 entities in total)
• Functional Keywords: dna damage response, brct, phosphopeptide, ligase-peptide complex, antitumor protein
• Biological source: Homo sapiens (Human); More
• Cellular location: Nucleus . Isoform 3: Cytoplasm. Isoform 5: Cytoplasm : P38398; Nucleus : Q6UWZ7
• Total number of polymer chains: 2
• Total formula weight: 26734.58

Authors

Wu, Q.,Blundell, T.L. (deposition date: 2015-02-09, release date: 2016-01-27, Last modification date: 2024-05-01)

Primary citation

Wu, Q.,Paul, A.,Su, D.,Mehmood, S.,Foo, T.K.,Ochi, T.,Bunting, E.L.,Xia, B.,Robinson, C.V.,Wang, B.,Blundell, T.L.
Structure of BRCA1-BRCT/Abraxas Complex Reveals Phosphorylation-Dependent BRCT Dimerization at DNA Damage Sites.
Mol.Cell, 61:434-448, 2016

PubMed Abstract: BRCA1 accumulation at DNA damage sites is an important step for its function in the DNA damage response and in DNA repair. BRCA1-BRCT domains bind to proteins containing the phosphorylated serine-proline-x-phenylalanine (pSPxF) motif including Abraxas, Bach1/FancJ, and CtIP. In this study, we demonstrate that ionizing radiation (IR)-induces ATM-dependent phosphorylation of serine 404 (S404) next to the pSPxF motif. Crystal structures of BRCT/Abraxas show that phosphorylation of S404 is important for extensive interactions through the N-terminal sequence outside the pSPxF motif and leads to formation of a stable dimer. Mutation of S404 leads to deficiency in BRCA1 accumulation at DNA damage sites and cellular sensitivity to IR. In addition, two germline mutations of BRCA1 are found to disrupt the dimer interface and dimer formation. Thus, we demonstrate a mechanism involving IR-induced phosphorylation and dimerization of the BRCT/Abraxas complex for regulating Abraxas-mediated recruitment of BRCA1 in response to IR.

PubMed: 26778126
DOI: 10.1016/j.molcel.2015.12.017

Experimental method

X-RAY DIFFRACTION (2.5 Å)