Figure 1.
3D structure of the HuPrP(125–228) α-fold used as template for the generation of the different mutants and sulfoxidized variants.
(A) 3D structure of the HuPrP(125–228) α-fold corresponding to the Pdb entry 1QLZ used as a starting point in the simulations [18] and depicting the different helical structures. (B) Side chains replaced for the generation of the different mutants used in this study.
Table 1.
Parameters of the HuPrP(125–228) chains used for the simulation.
Figure 2.
Effect of mutations on the residue based average flexibility.
Variation of the Root Mean Square Fluctuations (RMSF) as a function of the residue number for the different substituted protein forms: (A) D178N (blue), R208H (red); (B) E196K (blue), F198S (purple), E200K (cyan), V210I (red), E211Q (green); and (C) V180I (red), T183A (blue), T188K (green). For easiest comparison, the curve corresponding to the wt chain has been included in each panel as a black thick trace.
Figure 3.
Effect of methionine oxidation on the communication efficiency of all residues at increasing distances.
Each bin refers to a residue and shows the fraction of residues of the whole protein that are highly prone to communicate with it (CP<0.025). In each histogram only communications at distances greater than a given threshold: (<15 Å, black lines; >20 Å, red lines; >25 Å, green lines; and >30 Å, blue lines) are considered. From top to bottom: (A) wt, T188K, V210I, E211Q; (B) D178N, V180I, E196K; and (C) T183A, F198S, E200K, R208H.
Figure 4.
Effect of mutations and covalent modifications on the solvent exposure of α3-methionines.
Displayed SASA values for M205, M206 and M213 correspond to the difference SASAmut –SASAwt, where mut refers to mutant or covalently modified PrP chain and wt to wild type.
Figure 5.
Effect of mutations on the reactive regions and sites of HuPrP(125–228).
(A) Prediction of recognition regions by the MCLE analysis. The regions fulfilling the criteria for acting as interacting sites are depicted by colored boxes at their sequence position. The chain is indicated at the right. (B) 3D plot of the location of regions with interaction properties in the different HuPrP(121–228) variants.
Figure 6.
Dynamic diagnosis of PrP mutations.
HuPrP(121–228) fold displays interacting sites at regions located in α1 and in α2 (depicted in red) to which antibodies and small molecules behaving as conversion inhibitors bind. Presence of a pathogenic mutation or under conditions favoring the oxidation of the α3 methionines triggers a surface reactivity remodeling featured by the emergence of reactive features at the β2-α2 loop that dictates the engagement into the pathogenic route or that can be attenuated by its use as target for interference.