Microsecond sub-domain motions and the folding and misfolding of the mouse prion protein

  1. Rama Reddy Goluguri
  2. Sreemantee Sen
  3. Jayant Udgaonkar  Is a corresponding author
  1. Tata Institute of Fundamental Research, India

Abstract

Protein aggregation appear to originate from partially unfolded conformations that are sampled through stochastic fluctuations of the native protein. It has been a challenge to characterize these fluctuations, under native like conditions. Here, the conformational dynamics of the full-length (23-231) mouse prion protein were studied under native conditions, using photoinduced electron transfer coupled to fluorescence correlation spectroscopy (PET-FCS). The slowest fluctuations could be associated with the folding of the unfolded state to an intermediate state, by the use of microsecond mixing experiments. The two faster fluctuations observed by PET-FCS, could be attributed to fluctuations within the native state ensemble. The addition of salt, which is known to initiate the aggregation of the protein, resulted in an enhancement in the time scale of fluctuations in the core of the protein. The results indicate the importance of native state dynamics in initiating the aggregation of proteins.

Data availability

All data generated during the study are included in the manuscript and supporting files. Source data for Figures 2,3, 5, 6 and corresponding figure supplements have been uploaded as Excel file.

Article and author information

Author details

  1. Rama Reddy Goluguri

    National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bengaluru, India
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1134-9841
  2. Sreemantee Sen

    National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bengaluru, India
    Competing interests
    The authors declare that no competing interests exist.
  3. Jayant Udgaonkar

    National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bengaluru, India
    For correspondence
    jayant@iiserpune.ac.in
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7005-224X

Funding

Tata Institute of Fundamental Research

  • Rama Reddy Goluguri
  • Sreemantee Sen
  • Jayant Udgaonkar

Department of Science and Technology, Ministry of Science and Technology

  • Jayant Udgaonkar

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Hannes Neuweiler, University of Würzburg, Germany

Version history

  1. Received: December 29, 2018
  2. Accepted: April 25, 2019
  3. Accepted Manuscript published: April 26, 2019 (version 1)
  4. Version of Record published: May 14, 2019 (version 2)

Copyright

© 2019, Goluguri et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Rama Reddy Goluguri
  2. Sreemantee Sen
  3. Jayant Udgaonkar
(2019)
Microsecond sub-domain motions and the folding and misfolding of the mouse prion protein
eLife 8:e44766.
https://doi.org/10.7554/eLife.44766

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https://doi.org/10.7554/eLife.44766

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