4IFI

Structure of human BRCA1 BRCT in complex with BAAT peptide

4IFI の概要

• エントリーDOI: 10.2210/pdb4ifi/pdb
• 関連するPDBエントリー: 4IGK
• 分子名称: Breast cancer type 1 susceptibility protein, BAAT peptide, ACETATE ION, ... (4 entities in total)
• 機能のキーワード: cell cycle, disease mutation, dna damage, dna repair, fatty acid biosynthesis, ligase, lipid synthesis, metal-binding, nucleus, phosphoprotein, tumor suppressor, ubl conjugation pathway, zinc-finger, brct domain, dna damage response, phospho peptide interactions, dna-binding, phospho peptide binding, transcription
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Nucleus. Isoform 3: Cytoplasm. Isoform 5: Cytoplasm: P38398; Nucleus: Q6PJG6
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 25363.04

構造登録者

Liu, X.,Ladias, J.A.A. (登録日: 2012-12-14, 公開日: 2013-10-30, 最終更新日: 2024-11-27)

主引用文献

Liu, X.,Ladias, J.A.
Structural Basis for the BRCA1 BRCT Interaction with the Proteins ATRIP and BAAT1.
Biochemistry, 52:7618-7627, 2013

PubMed Abstract: The breast and ovarian cancer susceptibility protein 1 (BRCA1) plays a central role in DNA damage response (DDR). Two tandem BRCA1 C-terminal (BRCT) domains interact with several proteins that function in DDR and contain the generally accepted motif pS-X-X-F (pS denoting phosphoserine and X any amino acid), including the ATR-interacting protein (ATRIP) and the BRCA1-associated protein required for ATM activation-1 (BAAT1). The crystal structures of the BRCA1 BRCTs bound to the phosphopeptides ATRIP (235-PEACpSPQFG-243) and BAAT1 (266-VARpSPVFSS-274) were determined at 1.75 Å and 2.2 Å resolution, respectively. The pSer and Phe(+3) anchor the phosphopeptides into the BRCT binding groove, with adjacent peptide residues contributing to the interaction. In the BRCA1-ATRIP structure, Gln(+2) is accommodated through a conformational change of the BRCA1 E1698 side chain. Importantly, isothermal titration calorimetry experiments showed that the size and charge of the side chains at peptide positions +1 and +2 contribute significantly to the BRCA1 BRCT-peptide binding affinity. In particular, the Asp(+1) and Glu(+2) in the human CDC27 peptide 816-HAAEpSDEF-823 abrogate the interaction with the BRCA1 BRCTs due in large part to electrostatic repulsion between Glu(+2) and E1698, indicating a preference of these domains for specific side chains at positions +1 and +2. These results emphasize the need for a systematic assessment of the contribution of the peptide residues surrounding pSer and Phe(+3) to the binding affinity and specificity of the BRCA1 BRCTs in order to elucidate the molecular mechanisms underlying the hierarchy of target selection by these versatile domains during DDR and tumorigenesis.

PubMed: 24073851
DOI: 10.1021/bi400714v

実験手法

X-RAY DIFFRACTION (2.2 Å)