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

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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.

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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.

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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.

"This ORCID iD identifies the author of this article:" 0000-0003-1134-9841
Sreemantee Sen

National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bengaluru, India

Competing interests
The authors declare that no competing interests exist.
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.

"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.

Copyright

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.