title: Structure of human MDM2 complexed with RPL11 reveals the molecular basis of p53 activation.
abstract: The central region of MDM2 is critical for p53 activation and tumor suppression. Upon ribosomal stress, this region is bound by ribosomal proteins, particularly ribosomal protein L11 (RPL11), leading to MDM2 inactivation and subsequent p53 activation. Here, we solved the complex structure of human MDM2-RPL11 at 2.4 Å. MDM2 extensively interacts with RPL11 through an acidic domain and two zinc fingers. Formation of the MDM2-RPL11 complex induces substantial conformational changes in both proteins. RPL11, unable to bind MDM2 mutants, fails to induce the activation of p53 in cells. MDM2 mimics 28S rRNA binding to RPL11. The C4 zinc finger determines RPL11 binding to MDM2 but not its homolog, MDMX. Our results highlight the essential role of the RPL11-MDM2 interaction in p53 activation and tumor suppression and provide a structural basis for potential new anti-tumor drug development.
authors.affiliation: State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing 100193, China;
authors.forename: Jiangge
authors.initials: J
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing 100193, China; College of Veterinary Medicine, China Agricultural University, Beijing 100193, China;
authors.forename: Yue
authors.initials: Y
authors.lastname: Lang
authors.affiliation: State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing 100193, China;
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing 100193, China; College of Veterinary Medicine, China Agricultural University, Beijing 100193, China;
authors.forename: Di
authors.initials: D
authors.lastname: Cui
authors.affiliation: State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing 100193, China; College of Veterinary Medicine, China Agricultural University, Beijing 100193, China;
authors.forename: Haili
authors.initials: H
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing 100193, China;
authors.forename: Lun
authors.initials: L
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing 100193, China;
authors.forename: Zhenhang
authors.initials: Z
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing 100193, China; College of Veterinary Medicine, China Agricultural University, Beijing 100193, China;
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing 100193, China;
authors.forename: Yina
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Institute of Apicultural Research, Chinese Academy of Agricultural Sciences, Beijing 100093, China.
authors.forename: Wenli
authors.initials: W
authors.lastname: Tian
authors.affiliation: State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing 100193, China;
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing 100193, China; College of Veterinary Medicine, China Agricultural University, Beijing 100193, China;
authors.forename: Jun
authors.initials: J
authors.lastname: Tang
authors.affiliation: State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing 100193, China;
authors.forename: Zhongzhou
authors.initials: Z
authors.lastname: Chen
mesh_terms: D000595:Amino Acid Sequence; D003460:Crystallization; D020868:Gene Silencing; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry* / Q000235:genetics; D012269:Ribosomal Proteins / Q000737:chemistry*; D016415:Sequence Alignment; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D012269:Ribosomal Proteins; D016159:Tumor Suppressor Protein p53; C027624:ribosomal protein L11; D051736:Proto-Oncogene Proteins c-mdm2
keywords: RPL11—MDM2; cancer; complex structure; molecular basis; p53 activation