1hs5
NMR SOLUTION STRUCTURE OF DESIGNED P53 DIMER
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OverviewOverview
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.
DiseaseDisease
Known diseases associated with this structure: Adrenal cortical carcinoma OMIM:[191170], Breast cancer OMIM:[191170], Colorectal cancer OMIM:[191170], Hepatocellular carcinoma OMIM:[191170], Histiocytoma OMIM:[191170], Li-Fraumeni syndrome OMIM:[191170], Multiple malignancy syndrome OMIM:[191170], Nasopharyngeal carcinoma OMIM:[191170], Osteosarcoma OMIM:[191170], Pancreatic cancer OMIM:[191170], Thyroid carcinoma OMIM:[191170]
About this StructureAbout this Structure
1HS5 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
Structure and functionality of a designed p53 dimer., Davison TS, Nie X, Ma W, Lin Y, Kay C, Benchimol S, Arrowsmith CH, J Mol Biol. 2001 Mar 23;307(2):605-17. PMID:11254385
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