title: Pharmacological chaperone reshapes the energy landscape for folding and aggregation of the prion protein.
abstract: The development of small-molecule pharmacological chaperones as therapeutics for protein misfolding diseases has proven challenging, partly because their mechanism of action remains unclear. Here we study Fe-TMPyP, a tetrapyrrole that binds to the prion protein PrP and inhibits misfolding, examining its effects on PrP folding at the single-molecule level with force spectroscopy. Single PrP molecules are unfolded with and without Fe-TMPyP present using optical tweezers. Ligand binding to the native structure increases the unfolding force significantly and alters the transition state for unfolding, making it more brittle and raising the barrier height. Fe-TMPyP also binds the unfolded state, delaying native refolding. Furthermore, Fe-TMPyP binding blocks the formation of a stable misfolded dimer by interfering with intermolecular interactions, acting in a similar manner to some molecular chaperones. The ligand thus promotes native folding by stabilizing the native state while also suppressing interactions driving aggregation.
authors.affiliation: Department of Physics, University of Alberta, Edmonton, Alberta, Canada T6G 2E1.
authors.forename: Amar Nath
authors.initials: AN
authors.lastname: Gupta
authors.affiliation: Department of Physics, University of Alberta, Edmonton, Alberta, Canada T6G 2E1.
authors.forename: Krishna
authors.identifier: 0000-0003-1125-1924
authors.initials: K
authors.lastname: Neupane
authors.affiliation: Department of Physics, University of Alberta, Edmonton, Alberta, Canada T6G 2E1.
authors.forename: Negar
authors.initials: N
authors.lastname: Rezajooei
authors.affiliation: Division of Neurology, Department of Medicine, Centre for Prions and Protein Folding Diseases, and Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada T6G 2M8.
authors.forename: Leonardo M
authors.initials: LM
authors.lastname: Cortez
authors.affiliation: Division of Neurology, Department of Medicine, Centre for Prions and Protein Folding Diseases, and Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada T6G 2M8.
authors.forename: Valerie L
authors.initials: VL
authors.lastname: Sim
authors.affiliation: Department of Physics, University of Alberta, Edmonton, Alberta, Canada T6G 2E1.|National Institute for Nanotechnology, National Research Council, Edmonton, Alberta, Canada T6G 2M9.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Woodside
mesh_terms: D000818:Animals; D006224:Cricetinae; D008647:Mesocricetus; D008665:Metalloporphyrins / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000737:chemistry / Q000494:pharmacology*; D010446:Peptide Fragments / Q000737:chemistry*; D011328:Prions / Q000737:chemistry*; D011487:Protein Conformation; D017510:Protein Folding; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D008665:Metalloporphyrins; D018832:Molecular Chaperones; D010446:Peptide Fragments; D011328:Prions; D011758:Pyrroles; C507417:prion protein (90-231)