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The forkhead-associated (FHA) domain is a 55-75 amino acid residue module found
in >20 proteins from yeast to human. It has been suggested to participate in
signal transduction pathways, perhaps via protein-protein interactions involving
recognition of phosphopeptides. Neither the structure nor the ligand of FHA is
known. Yeast Rad53, a checkpoint protein involved in DNA damage response,
contains two FHA domains, FHA1 (residues 66-116) and FHA2 (residues 601-664),
the second of which recognizes phosphorylated Rad9. We herein report the
solution structure of an "FHA2-containing domain" of Rad53 (residues
573-730). The structure consists of a beta-sandwich containing two antiparallel
beta-sheets and a short, C-terminal alpha-helix. Binding experiments suggested
that the FHA2-containing domain specifically recognizes pTyr and a
pTyr-containing peptide from Rad9, and that the binding site involves residues
highly conserved across FHA domains. The results, along with other recent
reports, suggest that FHA domains could have pTyr and pSer/Thr dual specificity.
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