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Structure and Functionality of a Designed p53 Dimer.

2001

Article

ei


P53 is a homotetrameric tumor suppressor protein involved in transcriptional control of genes that regulate cell proliferation and death. In order to probe the role that oligomerization plays in this capacity, we have previously designed and characterized a series of p53 proteins with altered oligomeric states through hydrophilc substitution of residues Met340 or Leu344 in the normally tetrameric oligomerization domain. Although such mutations have little effect on the overall secondary structural content of the oligomerization domain, both solubility and the resistance to thermal denaturation are substantially reduced relative to that of the wild-type domain. Here, we report the design and characterization of a double-mutant p53 with alterations of residues at positions Met340 and Leu344. The double-mutations Met340Glu/Leu344Lys and Met340Gln/Leu344Arg resulted in distinct dimeric forms of the protein. Furthermore, we have verified by NMR structure determination that the double-mutant Met340Gln/Leu344Arg is essentially a "half-tetramer". Analysis of the in vivo activities of full-length p53 oligomeric mutants reveals that while cell-cycle arrest requires tetrameric p53, transcriptional transactivation activity of monomers and dimers retain roughly background and half of the wild-type activity, respectively.

Author(s): Davison, TS. and Nie, X. and Ma, W. and Lin, Y. and Kay, C. and Benchimol, S. and Arrowsmith, C.
Journal: Journal of Molecular Biology
Volume: 307
Number (issue): 2
Pages: 605-617
Year: 2001
Month: March
Day: 0

Department(s): Empirical Inference
Bibtex Type: Article (article)

Digital: 0
Institution: University of Toronto, Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, M5G 2M9, Canada.
Organization: Max-Planck-Gesellschaft
School: Biologische Kybernetik

Links: Web

BibTex

@article{3399,
  title = {Structure and Functionality of a Designed p53 Dimer.},
  author = {Davison, TS. and Nie, X. and Ma, W. and Lin, Y. and Kay, C. and Benchimol, S. and Arrowsmith, C.},
  journal = {Journal of Molecular Biology},
  volume = {307},
  number = {2},
  pages = {605-617},
  organization = {Max-Planck-Gesellschaft},
  institution = {University of Toronto, Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, M5G 2M9, Canada.},
  school = {Biologische Kybernetik},
  month = mar,
  year = {2001},
  month_numeric = {3}
}