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Article

Molecular Mechanism for Low pH Triggered Misfolding of the Human Prion Protein^†

Mari L. DeMarco and Valerie Daggett*

Department of Medicinal Chemistry, Biomolecular Structure and Design Program, University of Washington, Seattle, Washington 98195-7610

Biochemistry, 2007, 46 (11), pp 3045–3054

DOI: 10.1021/bi0619066

Publication Date (Web): February 22, 2007

†

We gratefully acknowledge partial support from the National Institutes of Health (Grant RO1 GM-50789 to V.D.) and a National Institute of General Medical Sciences National Research Service Award (Grant GM-07750) and the Hope Barnes Fellowship to M.L.D.

Corresponding author. E-mail: daggett@u.washington.edu. Phone: (206) 685-7420. Fax: 206-685-3252.

Abstract

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 (PrP^C), but it can misfold into a neurotoxic and infectious isoform (PrP^Sc). 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 PrP^Sc-like isoform consistent with our previous simulations of a smaller construct.

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