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Trainor K, Doyle CM, Metcalfe-Roach A, et al. Design for Solubility May Reveal Induction of Amide Hydrogen/Deuterium Exchange by Protein Self-Association. J Mol Biol. 2021;434(2):167398doi: 10.1016/j.jmb.2021.167398.
Trainor, K., Doyle, C. M., Metcalfe-Roach, A., Steckner, J., Lipovšek, D., Malakian, H., Langley, D., Krystek, S. R., & Meiering, E. M. (2022). Design for Solubility May Reveal Induction of Amide Hydrogen/Deuterium Exchange by Protein Self-Association. Journal of molecular biology, 434(2), 167398. https://doi.org/10.1016/j.jmb.2021.167398
Trainor, Kyle, et al. "Design for Solubility May Reveal Induction of Amide Hydrogen/Deuterium Exchange by Protein Self-Association." Journal of molecular biology vol. 434,2 (2022): 167398. doi: https://doi.org/10.1016/j.jmb.2021.167398
Trainor K, Doyle CM, Metcalfe-Roach A, Steckner J, Lipovšek D, Malakian H, Langley D, Krystek SR, Meiering EM. Design for Solubility May Reveal Induction of Amide Hydrogen/Deuterium Exchange by Protein Self-Association. J Mol Biol. 2022 Jan 30;434(2):167398. doi: 10.1016/j.jmb.2021.167398. Epub 2021 Dec 10. PMID: 34902431.
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J Mol Biol. 2022 Jan 30;434(2):167398. doi: 10.1016/j.jmb.2021.167398. Epub 2021 Dec 10.

Design for Solubility May Reveal Induction of Amide Hydrogen/Deuterium Exchange by Protein Self-Association.

Journal of molecular biology

Kyle Trainor, Colleen M Doyle, Avril Metcalfe-Roach, Julia Steckner, Daša Lipovšek, Heather Malakian, David Langley, Stanley R Krystek, Elizabeth M Meiering

Affiliations

  1. Department of Chemistry, University of Waterloo, Waterloo N2L 3G1, Ontario, Canada.
  2. Department of Chemistry, University of Waterloo, Waterloo N2L 3G1, Ontario, Canada. Electronic address: [email protected].
  3. Department of Chemistry, University of Waterloo, Waterloo N2L 3G1, Ontario, Canada. Electronic address: [email protected].
  4. Bristol Myers Squibb, Cambridge, MA 02140, United States. Electronic address: [email protected].
  5. Bristol Myers Squibb, Cambridge, MA 02140, United States.
  6. Department of Chemistry, University of Waterloo, Waterloo N2L 3G1, Ontario, Canada. Electronic address: [email protected].

PMID: 34902431 DOI: 10.1016/j.jmb.2021.167398

Abstract

Structural heterogeneity often constrains the characterization of aggregating proteins to indirect or low-resolution methods, obscuring mechanistic details of association. Here, we report progress in understanding the aggregation of Adnectins, engineered binding proteins with an immunoglobulin-like fold. We rationally design Adnectin solubility and measure amide hydrogen/deuterium exchange (HDX) under conditions that permit transient protein self-association. Protein-protein binding commonly slows rates of HDX; in contrast, we find that Adnectin association may induce faster HDX for certain amides, particularly in the C-terminal β-strand. In aggregation-prone proteins, we identify a pattern of very different rates of amide HDX for residues linked by reciprocal hydrogen bonds in the native structure. These results may be explained by local loss of native structure and formation of an inter-protein interface. Amide HDX induced by self-association, detected here by deliberate modulation of propensity for such interactions, may be a general phenomenon with the potential to expose mechanisms of aggregation by diverse proteins.

Copyright © 2021 Elsevier Ltd. All rights reserved.

Keywords: Adnectins; Amide hydrogen/deuterium exchange; aggregation; monobodies; protein solubility

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