ArticleProceedings of the National Academy of Sciences of the United States of America2014
Small molecule probes to quantify the functional fraction of a specific protein in a cell with minimal folding equilibrium shifts.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 34 citations in OpenAlex.
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- How synonymous mutations alter enzyme structure and function over long timescales.Nature chemistry · 2023Article
- Chemical Biology Framework to Illuminate Proteostasis.Annual review of biochemistry · 2020Review
- Molecular Determinants of Mutant Phenotypes, Inferred from Saturation Mutagenesis Data.Molecular biology and evolution · 2016Article
- Arylfluorosulfates Inactivate Intracellular Lipid Binding Protein(s) through Chemoselective SuFEx Reaction with a Binding Site Tyr Residue.Journal of the American Chemical Society · 2016Article
- Fluorescence Turn-On Folding Sensor To Monitor Proteome Stress in Live Cells.Journal of the American Chemical Society · 2015Article
- A fluorogenic aryl fluorosulfate for intraorganellar transthyretin imaging in living cells and in Caenorhabditis elegans.Journal of the American Chemical Society · 2015Article
- Individual and collective contributions of chaperoning and degradation to protein homeostasis in E. coli.Cell reports · 2015Article
- Modulation of the maladaptive stress response to manage diseases of protein folding.PLoS biology · 2014Article
- Probing the kinetic stabilities of Friedreich's ataxia clinical variants using a solid phase GroEL chaperonin capture platform.Biomolecules · 2014Article
- De novo-designed enzymes as small-molecule-regulated fluorescence imaging tags and fluorescent reporters.Journal of the American Chemical Society · 2014Article
- Heat-shock response transcriptional program enables high-yield and high-quality recombinant protein production in Escherichia coli.ACS chemical biology · 2014Article
Corrections and comments
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
Abstract
Although much is known about protein folding in buffers, it remains unclear how the cellular protein homeostasis network functions as a system to partition client proteins between folded and functional, soluble and misfolded, and aggregated conformations. Herein, we develop small molecule folding probes that specifically react with the folded and functional fraction of the protein of interest, enabling fluorescence-based quantification of this fraction in cell lysate at a time point of interest. Importantly, these probes minimally perturb a protein's folding equilibria within cells during and after cell lysis, because sufficient cellular chaperone/chaperonin holdase activity is created by rapid ATP depletion during cell lysis. The folding probe strategy and the faithful quantification of a particular protein's functional fraction are exemplified with retroaldolase, a de novo designed enzyme, and transthyretin, a nonenzyme protein. Our findings challenge the often invoked assumption that the soluble fraction of a client protein is fully folded in the cell. Moreover, our results reveal that the partitioning of destabilized retroaldolase and transthyretin mutants between the aforementioned conformational states is strongly influenced by cytosolic proteostasis network perturbations. Overall, our results suggest that applying a chemical folding probe strategy to other client proteins offers opportunities to reveal how the proteostasis network functions as a system to regulate the folding and function of individual client proteins in vivo.
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