Mechanistic Insights into Phosphoprotein-Binding FHA Domains
- 26 July 2008
- journal article
- review article
- Published by American Chemical Society (ACS) in Accounts of Chemical Research
- Vol. 41 (8), 991-999
- https://doi.org/10.1021/ar700148u
Abstract
FHA domains are protein modules that switch signals in diverse biological pathways by monitoring the phosphorylation of threonine residues of target proteins. As part of the effort to gain insight into cellular avoidance of cancer, FHA domains involved in the cellular response to DNA damage have been especially well-characterized. The complete protein where the FHA domain resides and the interaction partners determine the nature of the signaling. Thus, a key biochemical question is how do FHA domains pick out their partners from among thousands of alternatives in the cell? This Account discusses the structure, affinity, and specificity of FHA domains and the formation of their functional structure. Although FHA domains share sequence identity at only five loop residues, they all fold into a β-sandwich of two β-sheets. The conserved arginine and serine of the recognition loops recognize the phosphorylation of the threonine targeted. Side chains emanating from loops that join β-strand 4 with 5, 6 with 7, or 10 with 11 make specific contacts with amino acids of the ligand that tailor sequence preferences. Many FHA domains choose a partner in extended conformation, somewhat according to the residue three after the phosphothreonine in sequence (pT + 3 position). One group of FHA domains chooses a short carboxylate-containing side chain at pT + 3. Another group chooses a long, branched aliphatic side chain. A third group prefers other hydrophobic or uncharged polar side chains at pT + 3. However, another FHA domain instead chooses on the basis of pT − 2, pT − 3, and pT + 1 positions. An FHA domain from a marker of human cancer instead chooses a much longer protein fragment that adds a β-strand to its β-sheet and that presents hydrophobic residues from a novel helix to the usual recognition surface. This novel recognition site and more remote sites for the binding of other types of protein partners were predicted for the entire family of FHA domains by a bioinformatics approach. The phosphopeptide-dependent dynamics of an FHA domain, SH2 domain, and PTB domain suggest a common theme: rigid, preformed binding surfaces support van der Waals contacts that provide favorable binding enthalpy. Despite the lack of pronounced conformational changes in FHA domains linked to binding events, more subtle adjustments may be possible. In the one FHA domain tested, phosphothreonine peptide binding is accompanied by increased flexibility just outside the binding site and increased rigidity across the β-sandwich. The folding of the same FHA domain progresses through near-native intermediates that stabilize the recognition loops in the center of the phosphoprotein-binding surface; this may promote rigidity in the interface and affinity for targets phosphorylated on threonine.This publication has 36 references indexed in Scilit:
- Reading protein modifications with interaction domainsNature Reviews Molecular Cell Biology, 2006
- PhosphoThr Peptide Binding Globally Rigidifies Much of the FHA Domain from Arabidopsis Receptor Kinase-Associated Protein Phosphatase,Biochemistry, 2005
- Xrcc4 physically links DNA end processing by polynucleotide kinase to DNA ligation by DNA ligase IVThe EMBO Journal, 2004
- Crystal Structure of the FHA Domain of the Chfr Mitotic Checkpoint Protein and Its Complex with TungstateStructure, 2002
- The FHA domainFEBS Letters, 2001
- Structure of the FHA1 Domain of Yeast Rad53 and Identification of Binding Sites for both FHA1 and its Target Protein Rad9Journal of Molecular Biology, 2000
- DNA damage checkpoints and DNA replication controls in Saccharomyces cerevisiaeMutation Research - Reviews in Mutation Research, 2000
- Control of Meristem Development by CLAVATA1 Receptor Kinase and Kinase-Associated Protein Phosphatase Interactions1Plant Physiology, 1998
- Interaction of the maize and Arabidopsis kinase interaction domains with a subset of receptor‐like protein kinases: implications for transmembrane signaling in plantsThe Plant Journal, 1997
- The FHA domain: a putative nuclear signalling domain found in protein kinases and transcription factorsTrends in Biochemical Sciences, 1995