3I6W

Structure and Activation Mechanism of the CHK2 DNA-Damage Checkpoint Kinase

Summary for 3I6W

• Entry DOI: 10.2210/pdb3i6w/pdb
• Descriptor: Serine/threonine-protein kinase Chk2 (1 entity in total)
• Functional Keywords: ser/thr protein kinase, fha domain, atp-binding, cell cycle, disease mutation, kinase, li-fraumeni syndrome, magnesium, metal-binding, nucleotide-binding, nucleus, phosphoprotein, proto-oncogene, serine/threonine-protein kinase, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Isoform 2: Nucleus. Isoform 4: Nucleus. Isoform 7: Nucleus. Isoform 9: Nucleus. Isoform 12: Nucleus. Nucleus, PML body: O96017
• Total number of polymer chains: 8
• Total formula weight: 406719.56

Authors

Pavletich, N.P. (deposition date: 2009-07-07, release date: 2009-11-10, Last modification date: 2023-09-06)

Primary citation

Cai, Z.,Chehab, N.H.,Pavletich, N.P.
Structure and activation mechanism of the CHK2 DNA damage checkpoint kinase.
Mol.Cell, 35:818-829, 2009

PubMed Abstract: The CHK2 protein kinase is an important transducer of DNA damage checkpoint signals, and its mutation contributes to hereditary and sporadic cancer. CHK2 activation is triggered by the phosphorylation of Thr68 by the DNA damage-activated ATM kinase. This leads to transient CHK2 dimerization, in part through intermolecular phosphoThr68-FHA domain interactions. Dimerization promotes kinase activation through activation-loop autophosphorylation, but the mechanism of this process has not been clear. The dimeric crystal structure of CHK2, described here, in conjunction with biochemical and mutational data reveals that productive CHK2 dimerization additionally involves intermolecular FHA-kinase domain and FHA-FHA interactions. Ile157, mutated in the Li-Fraumeni cancer-predisposition syndrome, plays a central role in the FHA-kinase domain interface, explaining the lack of dimerization and autophosphorylation of this mutant. In the dimer, the kinase active sites face each other in close proximity, indicating that dimerization may also serve to optimally position the kinase active sites for efficient activation loop transphosphorylation.

PubMed: 19782031
DOI: 10.1016/j.molcel.2009.09.007

Experimental method

X-RAY DIFFRACTION (3.25 Å)