Phosphopeptide binding specificities of BRCA1 COOH-terminal (BRCT) domains.
Protein phosphorylation by protein kinases may generate docking sites for other proteins. It thus allows the assembly of signaling complexes in response to kinase activation. Several protein domains that bind phosphoserine or phosphothreonine residues have been identified, including the 14-3-3, PIN1, FHA, KIX, WD-40 domain, and polo box (Yaffe, M. ... B., and Elia, A. E. (2001) Curr. Opin. Cell Biol. 13, 131-138; Elia, A. E., Cantley, L. C., and Yaffe, M. B. (2003) Science 299, 1228-1231). The BRCA1 COOH-terminal (BRCT) domains are protein modules found in many proteins that regulate DNA damage responses (Koonin, E. V., Altschul, S. F., and Bork, P. (1996) Nat. Genet. 13, 266-268). Whether BRCT domains can mediate phosphorylation-dependent interactions has not been systematically investigated. We report here that the BRCT domains also recognize phosphopeptides. Oriented peptide library analysis indicated that the BRCT domains from BRCA1, MDC1, BARD1, and DNA Ligase IV preferred distinct phosphoserine-containing peptides. In addition, the interaction between BRCA1 and the BRCT binding motif of BACH1 was required for BACH1 checkpoint activity. Furthermore, BRCT domains of the yeast DNA repair protein Rad9 could bind phosphopeptides, suggesting that the BRCT domains represent a class of ancient phosphopeptide-binding modules. Potential targets of BRCT domains were identified through data base search. Structural analysis of BRCA1 BRCT repeats also predicted conserved residues that may form the phosphopeptide-binding pocket. Thus, the BRCT repeats are a new family of phosphopeptide-binding domains in DNA damage responses.
Mesh Terms:
Amino Acid Motifs, BRCA1 Protein, Basic-Leucine Zipper Transcription Factors, Carrier Proteins, Cell Cycle Proteins, DNA Damage, DNA Ligases, DNA Repair, DNA-Binding Proteins, Dose-Response Relationship, Drug, Dose-Response Relationship, Radiation, Fanconi Anemia Complementation Group Proteins, G2 Phase, Gene Library, Genes, BRCA1, Hela Cells, Humans, Microscopy, Fluorescence, Mitosis, Mutation, Nuclear Proteins, Peptides, Phosphorylation, Phosphoserine, Protein Binding, Protein Structure, Tertiary, RNA, Small Interfering, Signal Transduction, Trans-Activators, Transcription Factors, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases
Amino Acid Motifs, BRCA1 Protein, Basic-Leucine Zipper Transcription Factors, Carrier Proteins, Cell Cycle Proteins, DNA Damage, DNA Ligases, DNA Repair, DNA-Binding Proteins, Dose-Response Relationship, Drug, Dose-Response Relationship, Radiation, Fanconi Anemia Complementation Group Proteins, G2 Phase, Gene Library, Genes, BRCA1, Hela Cells, Humans, Microscopy, Fluorescence, Mitosis, Mutation, Nuclear Proteins, Peptides, Phosphorylation, Phosphoserine, Protein Binding, Protein Structure, Tertiary, RNA, Small Interfering, Signal Transduction, Trans-Activators, Transcription Factors, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases
J. Biol. Chem.
Date: Dec. 26, 2003
PubMed ID: 14578343
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