Structure of the BRCT repeats of BRCA1 bound to a BACH1 phosphopeptide: implications for signaling.
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.
Shiozaki
Eric N
EN
Department of Molecular Biology, Lewis Thomas Laboratory, Princeton University, Princeton, NJ 08544, USA.
Gu
Lichuan
L
Yan
Nieng
N
Shi
Yigong
Y
D019313:BRCA1 Protein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D050976:Basic-Leucine Zipper Transcription Factors; D001665:Binding Sites / Q000502:physiology; D001943:Breast Neoplasms / Q000235:genetics*; D002277:Carcinoma / Q000235:genetics*; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D051856:Fanconi Anemia Complementation Group Proteins; D005260:Female; D006801:Humans; D046911:Macromolecular Substances; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding / Q000502:physiology; D011487:Protein Conformation; D017434:Protein Structure, Tertiary / Q000502:physiology; D020449:Repetitive Sequences, Amino Acid / Q000502:physiology*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000737:chemistry* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
C102108:BACH1 protein, human; D019313:BRCA1 Protein; D050976:Basic-Leucine Zipper Transcription Factors; D051856:Fanconi Anemia Complementation Group Proteins; D046911:Macromolecular Substances; D010455:Peptides; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins