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Ligand-promoted protein folding by biased kinetic partitioning

Nature Chemical Biology volume 13, pages 369–371 (2017)Cite this article

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Abstract

Protein folding in cells occurs in the presence of high concentrations of endogenous binding partners, and exogenous binding partners have been exploited as pharmacological chaperones. A combined mathematical modeling and experimental approach shows that a ligand improves the folding of a destabilized protein by biasing the kinetic partitioning between folding and alternative fates (aggregation or degradation). Computationally predicted inhibition of test protein aggregation and degradation as a function of ligand concentration are validated by experiments in two disparate cellular systems.

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Figure 1: A model for the partitioning of protein among folding, aggregation, and degradation pathways.
Figure 2: The proteins studied and plots of fraction soluble protein remaining (Fr) vs. ligand concentration.

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Acknowledgements

We thank C.R. Matthews (University of Massachusetts Medical School, Worcester) for providing us with a plasmid containing the wild-type, cysteine-free E. coli DHFR gene. This work was supported by NIH grants GM101644 to L.M.G. and E.T.P. and DK76877 to S.C.G.

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Authors and Affiliations

  1. Program in Molecular and Cellular Biology, University of Massachusetts Amherst, Amherst, Massachusetts, USA

    Karan S Hingorani, Matthew C Metcalf, Derrick T Deming, Scott C Garman & Lila M Gierasch

  2. Department of Biochemistry & Molecular Biology, University of Massachusetts Amherst, Amherst, Massachusetts, USA

    Karan S Hingorani, Matthew C Metcalf, Derrick T Deming, Scott C Garman & Lila M Gierasch

  3. Department of Chemistry, The Scripps Research Institute, La Jolla, California, USA

    Evan T Powers

  4. Department of Chemistry, University of Massachusetts Amherst, Amherst, Massachusetts, USA

    Lila M Gierasch

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  1. Karan S Hingorani
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Contributions

K.S.H., L.M.G., E.T.P., and S.C.G. conceived the experiments. K.S.H. performed the experiments with dDHFR. K.S.H., M.C.M., and D.T.D. performed the experiments with R301Q α-GAL. E.T.P. developed the mathematical model. All authors contributed to the experimental design, data analysis, and manuscript preparation.

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Correspondence to Evan T Powers or Lila M Gierasch.

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The authors declare no competing financial interests.

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Supplementary Results, Supplementary Figures 1–5 and Supplementary Note. (PDF 1615 kb)

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Hingorani, K., Metcalf, M., Deming, D. et al. Ligand-promoted protein folding by biased kinetic partitioning. Nat Chem Biol 13, 369–371 (2017). https://doi.org/10.1038/nchembio.2303

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