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Sci. Signal., 29 May 2012
Vol. 5, Issue 226, p. ra39
[DOI: 10.1126/scisignal.2002979]


Editor's Summary

Fitting Protein Keys to Multiple Protein Locks
The ankyrin repeat motif is a 33-residue sequence that is important for mediating protein-protein interactions. ANKRA2 contains five such motifs, and it binds to histone deacetylase 4 (HDAC4), among other targets. Through peptide-binding arrays, mutagenesis studies, and x-ray crystallography, Xu et al. showed that the middle three ankyrin repeat domains of ANKRA2 form hydrophobic pockets that accommodate the linear arrangement of specific residues in the binding motif of HDAC4, similar to the way in which the tumblers of a lock accept a key. Phosphorylation of a serine residue within the ANKRA2-binding motif of HDAC4 attenuated the ANKRA2-HDAC4 interaction but enabled HDAC4 to bind to 14-3-3 proteins, which inhibit HDAC activity by sequestering HDACs in the cytoplasm. Proteome-wide screening identified other proteins with similar serine-containing, ankyrin domain–binding motifs, which suggests that phosphorylation acts as a switch that determines the binding preference of this motif in a signal-dependent manner.

Citation: C. Xu, J. Jin, C. Bian, R. Lam, R. Tian, R. Weist, L. You, J. Nie, A. Bochkarev, W. Tempel, C. S. Tan, G. A. Wasney, M. Vedadi, G. D. Gish, C. H. Arrowsmith, T. Pawson, X.-J. Yang, J. Min, Sequence-Specific Recognition of a PxLPxI/L Motif by an Ankyrin Repeat Tumbler Lock. Sci. Signal. 5, ra39 (2012).

Read the Full Text

Modular evolution of phosphorylation-based signalling systems.
J. Jin and T. Pawson (2012)
Phil Trans R Soc B 367, 2540-2555
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