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

@article{citeulike:2920355, abstract = {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 (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.}, address = {Department of Medicinal Chemistry, Biomolecular Structure and Design Program, University of Washington, Seattle, Washington 98195-7610}, author = {Demarco, M. L. and Daggett, V.}, citeulike-article-id = {2920355}, citeulike-linkout-0 = {http://dx.doi.org/10.1021/bi0619066}, citeulike-linkout-1 = {http://pubs.acs.org/doi/abs/10.1021/bi0619066}, day = {20}, doi = {10.1021/bi0619066}, journal = {Biochemistry}, keywords = {alkaline\_phosphatase, biochem\_lab}, month = {March}, number = {11}, pages = {3045--3054}, posted-at = {2008-06-24 07:15:52}, priority = {2}, title = {Molecular Mechanism for Low pH Triggered Misfolding of the Human Prion Protein}, url = {http://dx.doi.org/10.1021/bi0619066}, volume = {46}, year = {2007} }

TY - JOUR ID - citeulike:2920355 L3 - citeulike-article-id:2920355 N2 - 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 (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. IS - 11 JF - Biochemistry AD - Department of Medicinal Chemistry, Biomolecular Structure and Design Program, University of Washington, Seattle, Washington 98195-7610 EP - 3054 TI - Molecular Mechanism for Low pH Triggered Misfolding of the Human Prion Protein VL - 46 SP - 3045 KW - alkaline_phosphatase KW - biochem_lab AU - Demarco, ML AU - Daggett, V PY - 2007/03/20/ UR - http://dx.doi.org/10.1021/bi0619066 ER -