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Proc Natl Acad Sci U S A. 2019 Mar 26;116(13):6081-6090. doi: 10.1073/pnas.1819851116. Epub 2019 Mar 7.

Global analysis of methionine oxidation provides a census of folding stabilities for the human proteome.

Author information

1
Department of Biology, University of Rochester, NY 14627.
2
Department of Biochemistry, University of Rochester Medical Center, NY 14627.
3
Mass Spectrometry Resource Laboratory, University of Rochester Medical Center, NY 14627.
4
Department of Biology, University of Rochester, NY 14627; sina.ghaemmaghami@rochester.edu.

Abstract

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 highly multiplexed proteomics approach, based on analyses of methionine oxidation rates, to quantify stabilities of ∼10,000 unique regions within ∼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.

KEYWORDS:

intrinsically disordered proteins; methionine oxidation; osmolytes; protein folding; protein stability

PMID:
30846556
PMCID:
PMC6442572
DOI:
10.1073/pnas.1819851116
[Indexed for MEDLINE]
Free PMC Article

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