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Rescuing p53 from mdm2 by a pre-structured motif in intrinsically unfolded SUMO specific protease 4

  • Kim, Do-Hyoung (Korea Research Institute of Bioscience and Biotechnology) ;
  • Lee, Chewook (Korea Research Institute of Bioscience and Biotechnology) ;
  • Kim, Bom (Korea Research Institute of Bioscience and Biotechnology) ;
  • Lee, Si-Hyung (Korea Research Institute of Bioscience and Biotechnology) ;
  • Han, Kyou-Hoon (Korea Research Institute of Bioscience and Biotechnology)
  • Received : 2017.07.13
  • Published : 2017.10.31

Abstract

Many intrinsically unstructured/unfolded proteins (IUPs) contain transient local secondary structures even though they are "unstructured" in a tertiary sense. These local secondary structures are named "pre-structured motifs (PreSMos)" and in fact are the specificity determinants for IUP-target binding, i.e., the active sites in IUPs. Using high-resolution NMR we have delineated a PreSMo active site in the intrinsically unfolded mid-domain (residues 201-300) of SUMO-specific protease 4 (SUSP4). This 29-residue motif which we termed a p53 rescue motif can protect p53 from mdm2 quenching by binding to the p53-helix binding pocket in mdm2(3-109). Our work demonstrates that the PreSMo approach is quite effective in providing a structural rationale for interactions of p53-mdm2-SUSP4 and opens a novel avenue for designing mdm2-inhibiting anticancer compounds.

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