Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 116, Issue 13, Pages 6081-6090Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1819851116
Keywords
protein stability; protein folding; methionine oxidation; intrinsically disordered proteins; osmolytes
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Funding
- National Science Foundation [MCB-1350165 CAREER]
- National Institutes of Health [R35 GM119502-01, T32 GM068411, 1S100D021486-01, 1S10OD025242-01]
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The stability of proteins influences their tendency to aggregate, undergo degradation, or become modified in cells. Despite their significance to understanding protein folding and function, quantitative analyses of thermodynamic stabilities have been mostly limited to soluble proteins in purified systems. We have used a highlymultiplexed proteomics approach, based on analyses of methionine oxidation rates, to quantify stabilities of similar to 10,000 unique regionswithin similar to 3,000 proteins in human cell extracts. The data identify lysosomal and extracellular proteins as the most stable ontological subsets of the proteome. We show that the stability of proteins impacts their tendency to become oxidized and is globally altered by the osmolyte trimethylamine N-oxide (TMAO). We also show that most proteins designated as intrinsically disordered retain their unfolded structure in the complex environment of the cell. Together, the data provide a census of the stability of the human proteome and validate a methodology for global quantitation of folding thermodynamics.
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