Insight into the conserved structural dynamics of the C-terminus of mammal PrPC identifies structural core and possible structural role of pharmacological chaperones

ABSTRACT

Misfolding of the prion protein is central to prion disease aetiology. Although understanding the dynamics of the native fold helps to decipher the conformational conversion mechanism, a complete depiction of distal but coupled prion protein sites common across species is lacking. To fill this gap, we used normal mode analysis and network analysis to examine a collection of prion protein structures deposited on the protein data bank. Our study identified a core of conserved residues that sustains the connectivity across the C-terminus of the prion protein. We propose how a well-characterized pharmacological chaperone may stabilize the fold. Also, we provide insight into the effect on the native fold of initial misfolding pathways identified by others using kinetics studies.

KEYWORDS:

• Collective motions
• network analysis
• normal mode analysis
• Prion protein
• structural dynamics

Acknowledgments

The authors acknowledge valuable discussions with Rafayel Petrosyan. Resources were provided in part by the MERCURY consortium (http://mercuryconsortium.org/) under NSF grants CHE-1229354, CHE-1662030, and CHE-2018427.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Supplemental data

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19336896.2023.2186674

Additional information

Funding

This work was made possible partly by grants from the National Institute for General Medical Science (NIGMS) (5P20GM103427), a component of the National Institutes of Health (NIH), and its contents are the sole responsibility of the authors and do not necessarily represent the official views of NIGMS or NIH. The authors acknowledge the Creighton University Center for Undergraduate Research and Scholarship (CURAS) for partial funding.