期刊
JOURNAL OF CHEMICAL INFORMATION AND MODELING
卷 57, 期 2, 页码 223-233出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jcim.5b00409
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类别
资金
- Agence Nationale pour la Recherche (ANR Onco-KappaB)
- ANR
NF-kappa B is a major transcription factor whose activation is triggered through two main activation pathways: the canonical pathway involving disruption of I kappa B-alpha/NF-kappa B complexes and the alternative pathway whose activation relies on the inducible proteolysis of the inhibitory protein p100. One central step controlling p100 processing consists in the interaction of the E3 ubiquitin ligase beta-TrCP with p100, thereby leading to its ubiquitinylation and subsequent either complete degradation or partial proteolysis by the proteasome. However, the interaction mechanism between p100 and beta-TrCP is still poorly defined. In this work, a diphosphorylated 21-mer p100 peptide model containing the phosphodegron motif was used to characterize the interaction with beta-TrCP by NMR. In parallel, docking simulations were performed in order to obtain a model of the 21P-p100/beta-TrCP complex. Saturation transfer difference (STD) experiments were performed in order to highlight the residues of p100 involved in the interaction with the beta-TrCP protein. These results highlighted the importance of pSer(865) and. pSer(869) residues in the interaction with beta-TrCP and particularly the Tyr(867) that fits inside the hydrophobe fi-TrCP cavity with the Arg474 guanidinium group. Four other arginines, Arg285, Arg410, Arg431, and Arg521, were found essential in the stabilization of p100 on the beta-TrCP surface. Importantly, the requirement for these five arginine residues of beta-TrCP for the interaction with p100 was further confirmed in vivo, thereby validating the docking model through a biological approach.
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