Insight into the conserved structural dynamics of the C-terminus of mammal PrPC identifies structural core and possible structural role of pharmacological chaperones
Patricia Soto,
Garrett M. Gloeb,
Kaitlin A. Tsuchida,
Austin A. Charles,
Noah M. Greenwood,
Heidi Hendrickson
Affiliations
Patricia Soto
Physics department, Creighton University, Omaha, NE, USA
Garrett M. Gloeb
Chemistry department, Creighton University, Omaha, NE, USA
Kaitlin A. Tsuchida
Physics department, Creighton University, Omaha, NE, USA
Austin A. Charles
Chemistry department, Creighton University, Omaha, NE, USA
Noah M. Greenwood
Physics department, Creighton University, Omaha, NE, USA
Heidi Hendrickson
Chemistry department, Lafayette College, Easton, PA, USA
ABSTRACTMisfolding 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.
