Structural and Functional Analysis of Phosphothreonine-Dependent FHA Domain Interactions
Author(s)
Pennell, Simon; Westcott, Sarah; Ortiz-Lombardía, Miguel; Patel, Dony; Li, Jiejin; Nott, Timothy J.; Mohammed, Duaa; Buxton, Roger S.; Verma, Chandra; Smerdon, Stephen J.; Yaffe, Michael B; ... Show more Show less
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Summary:
FHA domains are well established as phospho-dependent binding modules mediating signal transduction in Ser/Thr kinase signaling networks in both eukaryotic and prokaryotic species. Although they are unique in binding exclusively to phosphothreonine, the basis for this discrimination over phosphoserine has remained elusive. Here, we attempt to dissect overall binding specificity at the molecular level. We first determined the optimal peptide sequence for Rv0020c FHA domain binding by oriented peptide library screening. This served as a basis for systematic mutagenic and binding analyses, allowing us to derive relative thermodynamic contributions of conserved protein and peptide residues to binding and specificity. Structures of phosphopeptide-bound and uncomplexed Rv0020c FHA domain then directed molecular dynamics simulations which show how the extraordinary discrimination in favor of phosphothreonine occurs through formation of additional hydrogen-bonding networks that are ultimately stabilized by van der Waals interactions of the phosphothreonine γ-methyl group with a conserved pocket on the FHA domain surface.
Date issued
2010-12Department
Massachusetts Institute of Technology. Department of Biology; Koch Institute for Integrative Cancer Research at MITJournal
Structure
Publisher
Elsevier B.V.
Citation
Pennell, Simon, Sarah Westcott, Miguel Ortiz-Lombardía, Dony Patel, Jiejin Li, Timothy J. Nott, Duaa Mohammed, et al. “Structural and Functional Analysis of Phosphothreonine-Dependent FHA Domain Interactions.” Structure 18, no. 12 (December 2010): 1587–1595. © 2010 Elsevier Ltd.
Version: Final published version
ISSN
09692126
1878-4186