title: The Mechanism of p53 Rescue by SUSP4.
abstract: p53 is an important tumor-suppressor protein deactivation of which by mdm2 results in cancers. A SUMO-specific protease 4 (SUSP4) was shown to rescue p53 from mdm2-mediated deactivation, but the mechanism is unknown. The discovery by NMR spectroscopy of a "p53 rescue motif" in SUSP4 that disrupts p53-mdm2 binding is presented. This 29-residue motif is pre-populated with two transient helices connected by a hydrophobic linker. The helix at the C-terminus binds to the well-known p53-binding pocket in mdm2 whereas the N-terminal helix serves as an affinity enhancer. The hydrophobic linker binds to a previously unidentified hydrophobic crevice in mdm2. Overall, SUSP4 appears to use two synergizing modules, the p53 rescue motif described here and a globular-structured SUMO-binding catalytic domain, to stabilize p53. A p53 rescue motif peptide exhibits an anti-tumor activity in cancer cell lines expressing wild-type p53. A pre-structures motif in the intrinsically disordered proteins is thus important for target recognition.
authors.affiliation: Genome Editing Research Center, Korea Research Institute of Bioscience and Biotechnology, 125, Gwahak-ro, Yuseong-gu, Daejeon, 34141, Korea.
authors.forename: Do-Hyoung
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Genome Editing Research Center, Korea Research Institute of Bioscience and Biotechnology, 125, Gwahak-ro, Yuseong-gu, Daejeon, 34141, Korea.
authors.forename: Chewook
authors.initials: C
authors.lastname: Lee
authors.affiliation: Genome Editing Research Center, Korea Research Institute of Bioscience and Biotechnology, 125, Gwahak-ro, Yuseong-gu, Daejeon, 34141, Korea.
authors.forename: Si-Hyung
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Molecular Epidemology Branch, Research Institute National Cancer Center, 323 Ilsandong-gu, Goyang-si, Gyeonggi-do, 10408, Korea.
authors.forename: Kyung-Tae
authors.initials: KT
authors.lastname: Kim
authors.affiliation: Genome Editing Research Center, Korea Research Institute of Bioscience and Biotechnology, 125, Gwahak-ro, Yuseong-gu, Daejeon, 34141, Korea.|College of Human Medicine, Michigan State University, East Lansing, MI, 48824, USA.
authors.forename: Joan J
authors.initials: JJ
authors.lastname: Han
authors.affiliation: Genome Editing Research Center, Korea Research Institute of Bioscience and Biotechnology, 125, Gwahak-ro, Yuseong-gu, Daejeon, 34141, Korea.
authors.forename: Eun-Ji
authors.initials: EJ
authors.lastname: Cha
authors.affiliation: Genome Editing Research Center, Korea Research Institute of Bioscience and Biotechnology, 125, Gwahak-ro, Yuseong-gu, Daejeon, 34141, Korea.
authors.forename: Ji-Eun
authors.initials: JE
authors.lastname: Lim
authors.affiliation: Genome Editing Research Center, Korea Research Institute of Bioscience and Biotechnology, 125, Gwahak-ro, Yuseong-gu, Daejeon, 34141, Korea.|Department of Bioinformatics, University of Science and Technology, 217, Gajeong-ro, Yuseong-gu, Daejoen, 34113, Korea.
authors.forename: Ye-Jin
authors.initials: YJ
authors.lastname: Cho
authors.affiliation: Division of Food Science and Culinary Art, Food and Nutrition Major, Shinhan University, 95 Hoam-ro, Uijeongbu-si, Gyeonggi-do, 11644, Korea.
authors.forename: Seung-Hee
authors.initials: SH
authors.lastname: Hong
authors.affiliation: Genome Editing Research Center, Korea Research Institute of Bioscience and Biotechnology, 125, Gwahak-ro, Yuseong-gu, Daejeon, 34141, Korea.|Department of Bioinformatics, University of Science and Technology, 217, Gajeong-ro, Yuseong-gu, Daejoen, 34113, Korea.
authors.forename: Kyou-Hoon
authors.initials: KH
authors.lastname: Han
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D056004:Molecular Dynamics Simulation; D016296:Mutagenesis; D010455:Peptides / Q000494:pharmacology; D011485:Protein Binding; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D010455:Peptides; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D003546:Cysteine Endopeptidases
keywords: NMR spectroscopy; SUSP4; intrinsically disordered protein; p53; pre-structured motif