Structural delineation of MDC1-FHA domain binding with CHK2-pThr68.
Mammalian MDC1 interacts with CHK2 in the regulation of DNA damage-induced S-phase checkpoint and apoptosis, which is directed by the association of MDC1-FHA and CHK2-pThr68. However, different ligand specificities of MDC1-FHA have been reported, and no structure is available. Here we report the crystal structures of MDC1-FHA and its complex with a CHK2 peptide containing pThr68. Unlike other FHA domains, MDC1-FHA exists as an intrinsic dimer in solution and in crystals. Structural and binding analyses support pThr+3 ligand specificity and provide structural insight into MDC1-CHK2 interaction.
Institute of Biological Chemistry, Academia Sinica, Nankang, Taipei 115, Taiwan.
Hsin-Hui
HH
Wu
Pei-Yu
PY
Wu
Kai-Fa
KF
Huang
Yu-Ya
YY
Kao
Ming-Daw
MD
Tsai
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D018797:Cell Cycle Proteins; D064447:Checkpoint Kinase 2; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000378:metabolism*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013912:Threonine / Q000378:metabolism*; D015534:Trans-Activators / Q000737:chemistry* / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C413163:MDC1 protein, human; D009687:Nuclear Proteins; D015534:Trans-Activators; D013912:Threonine; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; C578633:Chek2 protein, mouse; D017346:Protein Serine-Threonine Kinases