Transfer-NMR and docking studies identify the binding of the peptide derived from activating transcription factor 4 to protein ubiquitin ligase beta-TrCP. Competition STD-NMR with β-catenin.

ATF4 plays a crucial role in the cellular response to stress. The E3 ubiquitin ligase, SCF β-TrCP protein responsible for ATF4 degradation by the proteasome, binds to ATF4 through a DpSGXXXpS phosphorylation motif, which is similar but not identical to the DpSGXXpS motif found in most other substrates of β-TrCP. NMR studies were performed on the free and bound forms of a peptide derived from this ATF4 motif that enabled the elucidation of the conformation of the ligand complexed to the β-TrCP protein and its binding mode…  Docking studies showed that the ATF4 DpSGIXXpSXE motif fits the binding pocket of β-TrCP through an S-turning conformation. The distance between the two phosphate groups is 17.8 A, which matched the corresponding distance 17.1 A for the other extended DpSGXXpS motif in the β-TrCP receptor model. This study identifies the residues of the β-TrCP receptor involved in ligand recognition. Using a new concept of STD competition experiment, we show that ATF4 competes and inhibits binding of β-catenin to β-TrCP.

Julien Pons, Nathalie Evrard-Todeschi, Gildas Bertho, Josyane Gharbi-Benarous, Valérie Tanchou, Richard Benarous, Jean-Pierre Girault
January 8, 2008
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