3UNN

Monomeric structure of the human MDC1 FHA domain in complex with an MDC1 phospho-T4 peptide

3UNN の概要

• エントリーDOI: 10.2210/pdb3unn/pdb
• 関連するPDBエントリー: 3UMZ 3UNM
• 分子名称: Mediator of DNA damage checkpoint protein 1, phospho-T4 peptide from Mediator of DNA damage checkpoint protein 1 (3 entities in total)
• 機能のキーワード: fha, protein binding, phosphoprotein binding
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Nucleus : Q14676 Q14676
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 13511.43

構造登録者

Luo, S.,Ye, K. (登録日: 2011-11-16, 公開日: 2012-01-25, 最終更新日: 2024-11-20)

主引用文献

Liu, J.,Luo, S.,Zhao, H.,Liao, J.,Li, J.,Yang, C.,Xu, B.,Stern, D.F.,Xu, X.,Ye, K.
Structural mechanism of the phosphorylation-dependent dimerization of the MDC1 forkhead-associated domain
Nucleic Acids Res., 40:3898-3912, 2012

PubMed Abstract: MDC1 is a key mediator of the DNA-damage response in mammals with several phosphorylation-dependent protein interaction domains. The function of its N-terminal forkhead-associated (FHA) domain remains elusive. Here, we show with structural, biochemical and cellular data that the FHA domain mediates phosphorylation-dependent dimerization of MDC1 in response to DNA damage. Crystal structures of the FHA domain reveal a face-to-face dimer with pseudo-dyad symmetry. We found that the FHA domain recognizes phosphothreonine 4 (pT4) at the N-terminus of MDC1 and determined its crystal structure in complex with a pT4 peptide. Biochemical analysis further revealed that in the dimer, the FHA domain binds in trans to pT4 from the other subunit, which greatly stabilizes the otherwise unstable dimer. We show that T4 is phosphorylated primarily by ATM upon DNA damage. MDC1 mutants with the FHA domain deleted or impaired in its ability to dimerize formed fewer foci at DNA-damage sites, but the localization defect was largely rescued by an artificial dimerization module, suggesting that dimerization is the primary function of the MDC1 FHA domain. Our results suggest a novel mechanism for the regulation of MDC1 function through T4 phosphorylation and FHA-mediated dimerization.

PubMed: 22234877
DOI: 10.1093/nar/gkr1296

実験手法

X-RAY DIFFRACTION (1.7 Å)