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Structures of p53 cancer mutants and mechanism of rescue by second-site suppressor mutations.

Joerger AC, Ang HC, Veprintsev DB, Blair CM, Fersht AR
J Biol Chem 280 16030-7 (2005)
Related entries: 1tsr, 1tup, 1uol, 2bin, 2bio, 2bip, 2biq

Cited: 104 times
EuropePMC logo PMID: 15703170

Abstract

We have solved the crystal structures of three oncogenic mutants of the core domain of the human tumor suppressor p53. The mutations were introduced into a stabilized variant. The cancer hot spot mutation R273H simply removes an arginine involved in DNA binding without causing structural distortions in neighboring residues. In contrast, the "structural" oncogenic mutations H168R and R249S induce substantial structural perturbation around the mutation site in the L2 and L3 loops, respectively. H168R is a specific intragenic suppressor mutation for R249S. When both cancer mutations are combined in the same molecule, Arg(168) mimics the role of Arg(249) in wild type, and the wild type conformation is largely restored in both loops. Our structural and biophysical data provide compelling evidence for the mechanism of rescue of mutant p53 by intragenic suppressor mutations and reveal features by which proteins can adapt to deleterious mutations.

Reviews - 2bim mentioned but not cited (3)

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Reviews citing this publication (23)

  1. TP53 mutations in human cancers: origins, consequences, and clinical use. Olivier M, Hollstein M, Hainaut P. Cold Spring Harb Perspect Biol 2 a001008 (2010)
  2. Structural biology of the tumor suppressor p53. Joerger AC, Fersht AR. Annu Rev Biochem 77 557-582 (2008)
  3. The p53 Pathway: Origins, Inactivation in Cancer, and Emerging Therapeutic Approaches. Joerger AC, Fersht AR. Annu Rev Biochem 85 375-404 (2016)
  4. Structure-function-rescue: the diverse nature of common p53 cancer mutants. Joerger AC, Fersht AR. Oncogene 26 2226-2242 (2007)
  5. The tumor suppressor p53: from structures to drug discovery. Joerger AC, Fersht AR. Cold Spring Harb Perspect Biol 2 a000919 (2010)
  6. Cancer cell behaviors mediated by dysregulated pH dynamics at a glance. White KA, Grillo-Hill BK, Barber DL. J Cell Sci 130 663-669 (2017)
  7. Transcription regulation by mutant p53. Weisz L, Oren M, Rotter V. Oncogene 26 2202-2211 (2007)
  8. Reactivation of mutant p53: molecular mechanisms and therapeutic potential. Selivanova G, Wiman KG. Oncogene 26 2243-2254 (2007)
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  11. The aflatoxin-induced TP53 mutation at codon 249 (R249S): biomarker of exposure, early detection and target for therapy. Gouas D, Shi H, Hainaut P. Cancer Lett 286 29-37 (2009)
  12. The missing zinc: p53 misfolding and cancer. Loh SN. Metallomics 2 442-449 (2010)
  13. Transcriptional Regulation by Wild-Type and Cancer-Related Mutant Forms of p53. Pfister NT, Prives C. Cold Spring Harb Perspect Med 7 a026054 (2017)
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  16. Mutant p53 Protein and the Hippo Transducers YAP and TAZ: A Critical Oncogenic Node in Human Cancers. Ferraiuolo M, Verduci L, Blandino G, Strano S. Int J Mol Sci 18 E961 (2017)
  17. Key Players in the Mutant p53 Team: Small Molecules, Gene Editing, Immunotherapy. Chasov V, Mirgayazova R, Zmievskaya E, Khadiullina R, Valiullina A, Stephenson Clarke J, Rizvanov A, Baud MGJ, Bulatov E. Front Oncol 10 1460 (2020)
  18. TP53 in Biology and Treatment of Osteosarcoma. Synoradzki KJ, Bartnik E, Czarnecka AM, Fiedorowicz M, Firlej W, Brodziak A, Stasinska A, Rutkowski P, Grieb P. Cancers (Basel) 13 4284 (2021)
  19. Targeting p53 pathways: mechanisms, structures, and advances in therapy. Wang H, Guo M, Wei H, Chen Y. Signal Transduct Target Ther 8 92 (2023)
  20. Follow the Mutations: Toward Class-Specific, Small-Molecule Reactivation of p53. Loh SN. Biomolecules 10 E303 (2020)
  21. DNA-protein interaction: identification, prediction and data analysis. Emamjomeh A, Choobineh D, Hajieghrari B, MahdiNezhad N, Khodavirdipour A. Mol Biol Rep 46 3571-3596 (2019)
  22. How I Treat TP53-Mutated Acute Myeloid Leukemia and Myelodysplastic Syndromes. Loschi M, Fenaux P, Cluzeau T. Cancers (Basel) 14 4519 (2022)
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