Molecular mechanism for low pH triggered misfolding of the human prion protein.
Conformational changes in the prion protein cause transmissible spongiform encephalopathies, also referred to as prion diseases. In its native state, the prion protein is innocuous (PrPC), but it can misfold into a neurotoxic and infectious isoform (PrPSc). The full-length cellular form of the prion protein consists of residues 23-230, with over half of the sequence belonging to the unstructured N-terminal domain and the remaining residues forming a small globular domain. During misfolding and aggregation, portions of both the structured and unstructured domains are incorporated into the aggregates. After limited proteolysis by proteinase K, the most abundant fragment from brain-derived prion fibrils is a 141-residue fragment composed of residues 90-230. Here we describe simulations of this fragment of the human prion protein at low pH, which triggers misfolding, and at neutral pH as a control. The simulations, in agreement with experiment, show that this biologically and pathologically relevant prion construct is stable and native-like at neutral pH. In contrast, at low pH the prion protein is destabilized via disruption of critical long-range salt bridges. In one of the low pH simulations this destabilization resulted in a conformational transition to a PrPSc-like isoform consistent with our previous simulations of a smaller construct.
DeMarco
Mari L
ML
Department of Medicinal Chemistry, Biomolecular Structure and Design Program, University of Washington, Seattle, Washington 98195-7610, USA.
Daggett
Valerie
V
D000595:Amino Acid Sequence; D019295:Computational Biology; D003198:Computer Simulation; D006801:Humans; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D010446:Peptide Fragments / Q000737:chemistry*; D018620:PrPSc Proteins / Q000096:biosynthesis; D011328:Prions / Q000737:chemistry*; D011487:Protein Conformation / Q000187:drug effects; D017510:Protein Folding
D010446:Peptide Fragments; D018620:PrPSc Proteins; D011328:Prions; C514520:prion protein (91-231), human