 FHA Domain | |
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| Class:Phospho-Ser binding | |
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Structure:
 The FHA domain forms an 11-stranded b-sandwich that has a short a-helix inserted between b strands 2 and 3 and an alpha-helical region at the extreme C-terminus. The b-strand topology is essentially identical to that of the MH2 domain of Smad proteins, although the a-helical insertions involved in MH2 receptor binding and homo-oligomerization differ extensively. The N- and C-termini are in close proximity to one another since the first and last b strands in the sandwich lie adjacent to one another. The peptide binding site is located on the opposite side of the FHA domain, an arrangement that is consistent with the modular nature of an independent folding unit. The phosphothreonine peptide binds at a site created by the loop regions between b 3/4, b4/5, and b6/7, while regions not involved in creating the structural basis for these loops contain variable insertions and share little homology with one another. The figure presents the first FHA domain of Rad53 in complex with a phosphothreonine containing peptide. In this structure, the primary contact on the peptide occurs at the phosphothreonine and the +4 aspartic acid residue.
Structure Reference:
Durocher, D. et al. (2000) Mol. Cell. 6(5): 1169-1182. PDB: 1G6G.
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Domain binding and function:
The FHA domain, or Forkhead-Associated domain, was originally identified as a conserved region of forkhead transcription factors. FHA domains are ~65–100 amino acids long and form a β-sandwich fold consisting of a 3-stranded and a 4-stranded anti-parallel β sheet. While the N- and C terminal ends of the domain are located on adjacent β strands, the opposite side is bound by loops that act to coordinate phosphopeptide binding. FHA domains are found primarily in eukaryotic nuclear proteins that play a role in the DNA-damage response but are also found in certain prokaryotes, such as mycoplasma bacteria and mycobacterium tuberculosis. The FHA domain mediates phospho-peptide interactions with proteins phosphorylated by serine/threonine kinases. Most FHA domains recognize phospho-threonine with specificity provided by residues C-terminal to the phospho-threonine residue, particularly the +3 position. The FHA domains of Rad53 and PNK bind to pTXXD phospho-peptides.
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Examples of Proteins:
| PTB domain protein |
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Binding partner |
| Rad53 Yeast Ser/Thr Kinase |  |
Rad9 (phosphorylated) Yeast checkpoint control protein |
| KAPP Ser/Thr Phosphatase | |
pRLK5 (phosphorylated) Arabidopsis receptor-like Ser/Thr Kinase |
MDC1
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ATM, CHK2 Ser/Thr kinases
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Ki67
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hNIFK
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Polynucleotide Kinase (PNK)
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XRCC1 and XRCC4
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Referenced in part on Cell Signaling Technology Website, Reference Section on Protein Domains. We gratefully acknowledge the following contributors:
Piers Nash1, Dan Lin3, Kathleen Binns2, Clark Wells2, Rob Ingham2, Terry Kubiseski2, Bernard Liu1, Matt Smith2,3, Ivan Blasutig2,3, Maria Sierra1, Caesar Lim2,3, Michael Arc1, Jim Fawcett2 and Tony Pawson2,3.
1. Ben May Institute for Cancer Research, The University of Chicago, Chicago, Illinois, 60637, USA
2. Program in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, M5G 1X5, Canada
3. Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, M5S 1A8, Canada
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