The NMR solution structure of the oligomerization domain of the tumour suppressor p53 (residues 319-360) has been refined. The structure comprises a dimer of dimers, oriented in an approximately orthogonal manner. The present structure determination is based on 4,472 experimental NMR restraints which represents a three and half fold increase over our previous work in the number of NOE restraints at the tetramerization interface. A comparison with the recently solved 1.7 Å resolution X-ray structure shows that the structures are very similar and that the average angular root-mean-square difference in the interhelical angles is about 1°. The results of recent extensive mutagenesis data and the possible effects of mutations which have been identified in human cancers are discussed in the light of the present structure.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Nigro, J.M. et al. Mutations in the p53 gene occur in diverse human tumour types. Nature 342, 705–708 (1989).
Takahashi, T. et al. p53: A frequent target for genetic abnormalities in lung cancer. Science 246, 491–494 (1989).
Hollstein, M., Sidransky, B., Vogelstein, B. & Harris, C.C. p53 mutations in human cancers. Science 253, 49–53 (1991).
Lane, D.P. p53, guardian of the genome. Nature 358, 15–16 (1992).
Harris, C.C. p53: At the crossroads of molecular carcinogenesis and risk assessment. Science 262, 1980–1981 (1993).
Unger, T., Sau, M.M., Segal, S. & Minna, J.D. p53: A transdominant regulator of transcription whose function is ablated by mutations occuring in human cancer. EMBO J. 11, 1383–1390 (1992).
Prives, C. & Manfredi, J.J. The p53 tumoursuppresorprotein; Meeting review. Genes Develop. 7, 529–534 (1993).
Pavletich, N.P., Chambers, K.A. & Pabo, C.A., DMA-binding domain of p53 contains four conserved regions and the major mutation hot spots. Genes Develop. 7, 2556–2564 (1993).
Bargonetti, J., Manfredi, J.J., Chen, X., Marshak, D.R. & Prives, C. A proteolytic fragment from the central region of p53 has a marked sequence-specific DNA-binding activity when generated from wild-type but not oncogenic mutant p53 protein. Genes Develop. 7, 2565–2574 (1993).
Wang, Y. et al. p53 domains: Identification and characterization of two autonomous DNA binding regions. Genes Develop. 7, 2575–2586 (1993).
Cho, Y., Gorina, S., Jeffrey, P.D. & Pavletich, N.P. Crystal structure of a p53 tumour-suppressor-DNA complex; understanding tumorigenic mutations. Science 265, 346–355 (1994).
Clore, G.M. et al. High-resolution structure of the oligomerization domain of p53 by multidimensional NMR. Science 265, 386–391 (1994).
Clore, G.M. et al. Interhelical angles in the solution structure of the oligomerization domain of the tumour suppressor p53. Science (1995).
Lee, W. et al. Solution structure of the tetrameric minimum transforming domain of p53. Nature struct. Biol. 1, 877–890 (1994).
Jeffrey, P.D., Gorina, S. & Pavletich, N.P. Crystal structure of the tetramerization domain of the p53 tumor suppressor at 1. 7 Å. Science (1995).
Kuszewski, J., Qin, J., Gronenborn, A.M. & Clore, G.M. The impact of direct refinement against 13Cα and 13Cβ chemical shifts on protein structure determination by NMR. J. magn. Reson. B106, 92–96 (1995).
Grzesiek, S. & Bax, A. Measurement of amide proton exchange rates and NOEs with water in 13C/15N-enriched calcineurin B. J. biomolec. NMR 3, 627–638 (1993).
Clore, G.M., Bax, A., Omichinski, J.G. & Gronenborn, A.M. Localization of bound water in the solution structure of a complex of the erythroid transcription factor GATA-1 with DNA. Structure 2, 89–94 (1994).
Garrett, D.S. et al. The impact of direct refinement against three-bond HN-CαH coupling constants on protein structure determination by NMR. J. magn. Reson. B104, 99–103 (1994).
Clore, G.M., Robien, M.A. & Gronenborn, A.M. Exploring the limits of precision and accuracy of protein structures determined by nuclear magnetic resonance spectroscopy. J. molec. Biol. 231, 82–102 (1993).
Nilges, M., Clore, G.M. & Gronenborn, A.M. Determination of three-dimensional structures of proteins from interproton distance data by hybrid distance geometry-dynamical simulated annealing. FEBS Letts 239, 317–324 (1989).
Reiher, W.E. Theoretical studies of hydrogen bonding. Ph.D Thesis (Harvard University, Cambridge, MA; 1985).
Braun, W. & Go, N. Calculation of protein conformation by proton-proton distance constraints; a new efficient algorithm. J molec. Biol. 186, 611–626 (1985).
Momany, F.A., Carruthers, L.M., McGuire, R.F. & Scheraga, H.A. Intermolecular potentials from crystal data III. Determination of empirical potentials and application to the packing configurations and lattice energies in crystals of hydrocarbons, carboxylic acids and amides. J. phys. Chem. 78, 1595–1620 (1974).
Clubb, R.T., Omichinski, J.G., Sakaguchi, K., kApella, E., Gronenborn, A.M. & Clore, G.M. Backbone dynamics of the oligomerization domain of p53 determined from 15N NMR relaxation measurements. Prot. Sci. in the press.
Laskowski, R.A., MacArthur, M.W., Moss, D.S. & Thornton, J.M. PROCHECK; a program to check the stereochemical quality of protein structures. J. appl. Crystallogr 26, 283–291 (1993).
Kabsch, W. & Sander, C. Dictionary of protein secondary structre: pattern recognition of hydrogen-bonded and geometrical features. Biopolymers 22, 2577–2637 (1983).
Eisenberg, D. & MacLachlan, A.D. Solvation energy in protein folding and binding. Nature 319, 199–203 (1986).
Chiche, L., Gregoret, L.M., Cohen, F.E. & Kollman, P.A. Protein model structure evaluation using the solvation free energy of folding. Proc natn. Acad. Sci. U.S.A. 87, 3240–3243 (1990).
Vuister, G.W. & Bax, A. Quantitative J correlation: a new approach for measuring homonudear three-bond J(HNHα) couplings in 15N-enriched proteins. J. Am. chem. Soc. 115, 7772–7777 (1993).
Bax, A., Max, D. & Zax, D. Measurement of multiple-bond 13C-13C J couplings in a 20 kDa protein-peptide complex. J. Am. chem. Soc. 114, 6923–6924 (1992).
Stürzbecher, W.W. et al. A C-terminal α-helix plus basic region motif is the major structural determinant of p53 tetramerization. Oncogene 7, 1513–1523 (1992).
Sakamoto, H., Lewis, M.S., Kodoma, H., Appella, E. & Sakaguchi, K. Specific sequences from the carboxyl terminus of the human p53 gene product form anti-parallel tetramers in solution. Proc. natn. Acad. Sci. U.S.A. 91, 8974–8978 (1994).
Waterman, J.L., Shenk, J.L. & Halazonetis, T.D. The dihedral symmetry of the p53 tetramerization domain mandates a conformational switch upon DNA binding. EMBO J. 14, 512–519 (1995).
Creamer, T.P. & Rose, G.D Side-chain entropy opposes α-helix formation but rationalizes experimentally determined helix-forming propensities. Proc. natn. Acad. Sci. U.S.A. 89, 5937–5941 (1992)
Handel, T.M., Williams, S.R. & DeGrado, W.F. Metal-ion dependent modulation of the dynamics of a designed protein. Science 261, 879–885 (1993).
Cariello, N.F., Cui, L., Beroud, C. & Soussi, T. Database and software for the analysis of mutations in the human p53 gene. Cancer Res. 54, 4454–4460 (1994).
Harper, E.T. & Rose, G.D. Helix stop signals in proteins and peptides: the capping box. Biochemistry 32, 7605–7609 (1993).
Milner, J. & Medcalf, E.A. Cotranslation of activated mutant p53 with wild type drives the wild-type p53 protein into the mutant conformation. Cell 65, 765–774 (1991).
Bargonetti, J., Reynisdottir, J., Friedman, P.N. & Prives, C. Site specific binding of wild-type p53 to cellular DNA is inhibited by SV40 T antigen and mutant p53. Genes Develop. 6, 1886–1898 (1992).
Shaulian, E., Zauberman, A., Ginsberg, D. & Oren, M. Identification of a minimal transforming domain of p53: negative dominance through the abrogation of sequence-specific DNA binding. Molec. cell Biol. 12, 5581–5592 (1992).
Halazonetis, T.D. & Kandil, A.N. Conformational shifts propogate from the oligomerization domain of p53 to its tetrameric DNA binding domain and restore DNA binding to select p53 mutants. EMBO J. 12, 5057–5064 (1993).
Hainaut, P., Hall, A. & Milner, J. Analysis of p53 quaternary structure in relation to sequence specific DNA binding. Oncogene 9, 299–303 (1994).
Ziegler, A. et al. Sunburn and p53 in the onset of skin cancer. Nature 372, 773–776 (1994).
Aurora, R., Srinivasan, R. & Rose, G.D. Rules for α-helix termination by glycine. Science 264, 1126–1130 (1994).
Soussi, T., de Fromentel, C.C. & May, P. Structural aspects of the p53 protein in relation to gene evolution. Oncogene 5, 945–952.
Dayhoff, M.O. Atlas of Sequence and Strucfure (National Biomedical Research Foundation, Silver Spring, U.S.A.; 1969).
Bodenhausen, G. & Ruben, D.J. Natural abundance nitrogen-15 NMR by enhanced heteronuclear spectroscopy. Chem. Phys Letts 69, 185–189 (1980).
Yamazaki, T. et al. NMR and X-ray evidence that the HIV protease catalytic aspartyl groups are protonated in the complex formed by the protease and a non-peptide cyclic urea-based inhibitor. J. Am. chem. Soc 116, 10791–10792 (1994).
Brünger, A.T. X-PLOR Version 3.1 Manual (Yale University, New Haven, CT, U.S.A.; 1992).
Nilges, M. A calculational strategy for the structure determination of symmetric dimers by 1H NMR. Proteins Struct. Funct. Genet. 17, 295–309 (1993).
Clore, G.M., Appella, E., Yamada, M., Matsushima, K. & Gronenborn, A.M. Three-dimensional structure of interelukin-8 in solution. Biochemistry 29, 1689–1696 (1990).
Kraulis, P.J. et al. Determination of the three-dimensional solution structure of the C-terminal domain of cellobiohydrolase I from Trichoderma reesei: a study using nuclear magnetic resonance and hybrid distance geometry-dynamical simulated annealing. Biochemistry 28, 7241–7257 (1989).
Brünger, A.T. & DeLano, W. AVSXPLOR User Manual, Yale University, New Haven, CT, U.S.A. (1992).
Carson, M. Ribbon models of macromolecules. J. molec. Graphics 5, 103–106 (1987).
de Castro, E. & Edelstein, S. VISP 1.0 User's Guide (University of Geneva, Switzerland; 1992).
Brooks, B.R. et al. CHARMM: a program for macromolecular energy minimization and dynamics calculations. J. comput. Chem. 4, 187–217 (1983).
Richards, P.M. & Kundrot, C.E. Identification of structural motifs from protein coordinate data: secondary structure and first level supersecondary structure. Proteins Struct. Funct. Genet. 3, 71–84.
Lodi, P.J. et al. High-resolution structure of the β-chemokine hMIP-1β by multidimensional NMR. Science 263, 1762–1767 (1994).
About this article
Nature Reviews Molecular Cell Biology (2019)
Oligomerization enhances the binding affinity of a silver biomineralization peptide and catalyzes nanostructure formation
Scientific Reports (2017)
Scientific Reports (2017)
Nature Biotechnology (2012)
The EMBO Journal (2011)