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Title: Unfolded states under folding conditions accommodate sequence-specific conformational preferences with random coil-like dimensions

Abstract

Proteins are marginally stable molecules that fluctuate between folded and unfolded states. Here, we provide a high-resolution description of unfolded states under refolding conditions for the N-terminal domain of the L9 protein (NTL9). We use a combination of time-resolved Förster resonance energy transfer (FRET) based on multiple pairs of minimally perturbing labels, time-resolved small-angle X-ray scattering (SAXS), all-atom simulations, and polymer theory. Upon dilution from high denaturant, the unfolded state undergoes rapid contraction. Although this contraction occurs before the folding transition, the unfolded state remains considerably more expanded than the folded state and accommodates a range of local and nonlocal contacts, including secondary structures and native and nonnative interactions. Paradoxically, despite discernible sequence-specific conformational preferences, the ensemble-averaged properties of unfolded states are consistent with those of canonical random coils, namely polymers in indifferent (theta) solvents. These findings are concordant with theoretical predictions based on coarse-grained models and inferences drawn from single-molecule experiments regarding the sequence-specific scaling behavior of unfolded proteins under folding conditions.

Authors:
 [1]; ORCiD logo [2];  [1]; ORCiD logo [2];  [3];  [4]
  1. Stony Brook Univ., NY (United States). Dept. of Chemistry
  2. Washington Univ., St. Louis, MO (United States)
  3. Univ. of Massachusetts, Worcester, MA (United States)
  4. Stony Brook Univ., NY (United States). Dept. of Chemistry; Univ. College London (United Kingdom)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
National Institutes of Health (NIH)
OSTI Identifier:
1545860
Grant/Contract Number:  
[AC02-06CH11357]
Resource Type:
Accepted Manuscript
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
[ Journal Volume: 116; Journal Issue: 25]; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences
Country of Publication:
United States
Language:
ENGLISH
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 59 BASIC BIOLOGICAL SCIENCES; protein folding; unfolded state; FRET; compaction transition

Citation Formats

Peran, Ivan, Holehouse, Alex S., Carrico, Isaac S., Pappu, Rohit V., Bilsel, Osman, and Raleigh, Daniel P. Unfolded states under folding conditions accommodate sequence-specific conformational preferences with random coil-like dimensions. United States: N. p., 2019. Web. doi:10.1073/pnas.1818206116.
Peran, Ivan, Holehouse, Alex S., Carrico, Isaac S., Pappu, Rohit V., Bilsel, Osman, & Raleigh, Daniel P. Unfolded states under folding conditions accommodate sequence-specific conformational preferences with random coil-like dimensions. United States. doi:10.1073/pnas.1818206116.
Peran, Ivan, Holehouse, Alex S., Carrico, Isaac S., Pappu, Rohit V., Bilsel, Osman, and Raleigh, Daniel P. Wed . "Unfolded states under folding conditions accommodate sequence-specific conformational preferences with random coil-like dimensions". United States. doi:10.1073/pnas.1818206116.
@article{osti_1545860,
title = {Unfolded states under folding conditions accommodate sequence-specific conformational preferences with random coil-like dimensions},
author = {Peran, Ivan and Holehouse, Alex S. and Carrico, Isaac S. and Pappu, Rohit V. and Bilsel, Osman and Raleigh, Daniel P.},
abstractNote = {Proteins are marginally stable molecules that fluctuate between folded and unfolded states. Here, we provide a high-resolution description of unfolded states under refolding conditions for the N-terminal domain of the L9 protein (NTL9). We use a combination of time-resolved Förster resonance energy transfer (FRET) based on multiple pairs of minimally perturbing labels, time-resolved small-angle X-ray scattering (SAXS), all-atom simulations, and polymer theory. Upon dilution from high denaturant, the unfolded state undergoes rapid contraction. Although this contraction occurs before the folding transition, the unfolded state remains considerably more expanded than the folded state and accommodates a range of local and nonlocal contacts, including secondary structures and native and nonnative interactions. Paradoxically, despite discernible sequence-specific conformational preferences, the ensemble-averaged properties of unfolded states are consistent with those of canonical random coils, namely polymers in indifferent (theta) solvents. These findings are concordant with theoretical predictions based on coarse-grained models and inferences drawn from single-molecule experiments regarding the sequence-specific scaling behavior of unfolded proteins under folding conditions.},
doi = {10.1073/pnas.1818206116},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = [25],
volume = [116],
place = {United States},
year = {2019},
month = {6}
}

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    Fine Structure Analysis of a Protein Folding Transition State; Distinguishing Between Hydrophobic Stabilization and Specific Packing
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    Probing the Action of Chemical Denaturant on an Intrinsically Disordered Protein by Simulation and Experiment
    journal, September 2016

    • Zheng, Wenwei; Borgia, Alessandro; Buholzer, Karin
    • Journal of the American Chemical Society, Vol. 138, Issue 36
    • DOI: 10.1021/jacs.6b05443

    Collapse Precedes Folding in Denaturant-Dependent Assembly of Ubiquitin
    journal, January 2017


    Proline-Rich Salivary Proteins Have Extended Conformations
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    Robust, high-throughput solution structural analyses by small angle X-ray scattering (SAXS)
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    • Hura, Greg L.; Menon, Angeli L.; Hammel, Michal
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    • Cho, J. -H.; Meng, W.; Sato, S.
    • Proceedings of the National Academy of Sciences, Vol. 111, Issue 33
    • DOI: 10.1073/pnas.1402054111

    Single-molecule spectroscopy reveals polymer effects of disordered proteins in crowded environments
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