Silvia Lisa Massimiliano Meli Gema Cabello Ruth Gabizon Giorgio Colombo María Gasset +34-915619400 +34-915612431 mgasset@iqfr.csic.es Insto Química-Física “Rocasolano”, CSIC Serrano 119 28006 Madrid Spain Istituto di Chimica del Riconoscimento Molecolare, Consiglio Nazionale delle Ricerche Via Mario Bianco 9 20131 Milan Italy Department of Neurology, The Agnes Ginges Center for Human Neurogenetics Hadassah University Hospital 91120 Jerusalem Israel Abstract The conversion of the cellular prion protein (PrP C ) into its disease-associated form (PrP Sc ) 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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The structural intolerance of the PrP α-fold for polar substitution of the helix-3 methionines
Silvia, Lisa; Massimiliano, Meli; Gema, Cabello; Ruth, Gabizon; Giorgio, Colombo; María, Gasset
Follow Cellular and Molecular Life Sciences
, Volume 67 (16)
Springer Journals – Aug 1, 2010
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