Structural and functional versatility of the FHA domain in DNA-damage signaling by the tumor suppressor kinase Chk2.
The Chk2 Ser/Thr kinase plays crucial, evolutionarily conserved roles in cellular responses to DNA damage. Identification of two pro-oncogenic mutations within the Chk2 FHA domain has highlighted its importance for Chk2 function in checkpoint activation. The X-ray structure of the Chk2 FHA domain in complex with an in vitro selected phosphopeptide motif reveals the determinants of binding specificity and shows that both mutations are remote from the peptide binding site. We show that the Chk2 FHA domain mediates ATM-dependent Chk2 phosphorylation and targeting of Chk2 to in vivo binding partners such as BRCA1 through either or both of two structurally distinct mechanisms. Although phospho-dependent binding is important for Chk2 activity, previously uncharacterized phospho-independent FHA domain interactions appear to be the primary target of oncogenic lesions.
Li
Jiejin
J
Division of Protein Structure, National Institute for Medical Research, The Ridgeway, Mill Hill, London, United Kingdom.
Williams
Brandi L
BL
Haire
Lesley F
LF
Goldberg
Michal
M
Wilker
Erik
E
Durocher
Daniel
D
Yaffe
Michael B
MB
Jackson
Stephen P
SP
Smerdon
Stephen J
SJ
D000595:Amino Acid Sequence; D019313:BRCA1 Protein / Q000378:metabolism; D064447:Checkpoint Kinase 2; D018360:Crystallography, X-Ray; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism; D051858:Forkhead Transcription Factors; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins; D019151:Peptide Library; D010449:Peptide Mapping; D010766:Phosphorylation; D011485:Protein Binding; D011494:Protein Kinases / Q000235:genetics / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases; D017434:Protein Structure, Tertiary; D051785:Smad Proteins; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors
D019313:BRCA1 Protein; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; D009687:Nuclear Proteins; D019151:Peptide Library; D051785:Smad Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases