The structural intolerance of the PrP α-fold for polar substitution of the helix-3 methionines |
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Authors: | Silvia Lisa Massimiliano Meli Gema Cabello Ruth Gabizon Giorgio Colombo María Gasset |
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Institution: | 1. Insto Química-Física “Rocasolano”, CSIC, Serrano 119, 28006, Madrid, Spain 2. Istituto di Chimica del Riconoscimento Molecolare, Consiglio Nazionale delle Ricerche, Via Mario Bianco 9, 20131, Milan, Italy 3. Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah University Hospital, 91120, Jerusalem, Israel
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Abstract: | The conversion of the cellular prion protein (PrPC) into its disease-associated form (PrPSc) involves a major conformational change and the accumulation of sulfoxidized methionines. Computational and synthetic approaches
have shown that this change in the polarity of M206 and M213 impacts the C-terminal domain native α-fold allowing the flexibility
required for the structural conversion. To test the effect in the full-length molecule with site-specificity, we have generated
M-to-S mutations. Molecular dynamics simulations show that the replacement indeed perturbs the native state. When this mutation
is placed at the conserved methionines of HaPrP(23–231), only substitutions at the Helix-3 impair the α-fold, stabilizing
a non-native state with perturbed secondary structure, loss of native tertiary contacts, increased surface hydrophobicity,
reduced thermal stability and an enhanced tendency to aggregate into protofibrillar polymers. Our work supports that M206
and M213 function as α-fold gatekeepers and suggests that their redox state regulate misfolding routes. |
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