Characterization of the oligomerization defects of two p53 mutants found in families with Li-Fraumeni and Li-Fraumeni-like syndrome.
Recently two germline mutations in the oligomerization domain of p53 have been identified in patients with Li-Fraumeni and Li-Fraumeni-like Syndromes. We have used biophysical and biochemical methods to characterize these two mutants in order to better understand their functional defects and the role of the p53 oligomerization domain (residues 325-355) in oncogenesis. We find that residues 310-360 of the L344P mutant are monomeric, apparently unfolded and cannot interact with wild-type (WT) p53. The full length L344P protein is unable to bind sequence specifically to DNA and is therefore an inactive, but not a dominant negative mutant. R337C, on the other hand, can form dimers and tetramers, can hetero-oligomerize with WTp53 and can bind to a p53 consensus element. However, the thermal stability of R337C is much lower than that of WTp53 and at physiological temperatures more than half of this mutant is less than tetrameric. Thus, the R337C mutant retains some functional activity yet leads to a predisposition to cancer, suggesting that even partial inactivation of p53 oligomerization is sufficient for accelerated tumour progression.
Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, Ontario, Canada.
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Davison
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Yin
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Nie
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Kay
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Arrowsmith
D001120:Arginine / Q000235:genetics / Q000502:physiology*; D002942:Circular Dichroism; D003545:Cysteine / Q000235:genetics / Q000502:physiology*; D018095:Germ-Line Mutation; D006801:Humans; D007930:Leucine / Q000235:genetics / Q000502:physiology*; D016864:Li-Fraumeni Syndrome / Q000235:genetics / Q000378:metabolism*; D019906:Nuclear Magnetic Resonance, Biomolecular; D011392:Proline / Q000235:genetics / Q000502:physiology*; D017433:Protein Structure, Secondary; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*
D016159:Tumor Suppressor Protein p53; D001120:Arginine; D011392:Proline; D007930:Leucine; D003545:Cysteine