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Identification of two reactive cysteine residues in the tumor suppressor protein p53 using top-down FTICR mass spectrometry
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Scotcher, Jenna, Clarke, D. J., Weidt, Stefan K., Mackay, C. Logan, Hupp, Theodore, Sadler, P. J. and Langridge-Smith, Pat R. R. (2011) Identification of two reactive cysteine residues in the tumor suppressor protein p53 using top-down FTICR mass spectrometry. Journal of The American Society for Mass Spectrometry, Vol.22 (No.5). pp. 888-897. doi:10.1007/s13361-011-0088-x ISSN 1044-0305.
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Official URL: http://dx.doi.org/10.1007/s13361-011-0088-x
Abstract
The tumor suppressor p53 is a redox-regulated transcription factor involved in cell cycle arrest, apoptosis and senescence in response to multiple forms of stress, as well as many other cellular processes such as DNA repair, glycolysis, autophagy, oxidative stress and differentiation. The discovery of cysteine-targeting compounds that cause re-activation of mutant p53 and the death of tumor cells in vivo has emphasised the functional importance of p53 thiols. Using a combination of top-down and middle-down FTICR mass spectrometry, we show that of the 10 Cys residues in the core domain of wild-type p53, Cys182 and Cys277 exhibit a remarkable preference for modification by the alkylating reagent N-ethylmaleimide. The assignment of Cys182 and Cys277 as the two reactive Cys residues was confirmed by site-directed mutagenesis. Further alkylation of p53 beyond Cys182 and Cys277 was found to trigger co-operative modification of the remaining seven Cys residues and protein unfolding. This study highlights the power of top-down FTICR mass spectrometry for analysis of the cysteine reactivity
and redox chemistry in multiple cysteine-containing proteins.
Item Type: | Journal Article | ||||
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Subjects: | Q Science > QD Chemistry Q Science > QP Physiology |
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry | ||||
Library of Congress Subject Headings (LCSH): | Tumor suppressor proteins, p53 protein, Fourier transform spectroscopy, Mass spectroscopy, Fragmentation reactions, Cysteine proteinases | ||||
Journal or Publication Title: | Journal of The American Society for Mass Spectrometry | ||||
Publisher: | Springer New York LLC | ||||
ISSN: | 1044-0305 | ||||
Official Date: | May 2011 | ||||
Dates: |
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Volume: | Vol.22 | ||||
Number: | No.5 | ||||
Page Range: | pp. 888-897 | ||||
DOI: | 10.1007/s13361-011-0088-x | ||||
Status: | Peer Reviewed | ||||
Publication Status: | Published | ||||
Access rights to Published version: | Restricted or Subscription Access | ||||
Funder: | Research Councils UK (RCUK) |
Data sourced from Thomson Reuters' Web of Knowledge
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