Human prion proteins and mutants through the lens of systems biology

Network analyses of wild-type human prion protein and five point mutants identify Met206, Val209, Val210, Met213, and Cys214 as consistently high-centrality residues linked to disrupted connectivity and misfolding propensity.

• Why it matters: The molecular mechanisms driving PrPC to the β-sheet-enriched PrPSC scrapie isoform in human prion diseases remain unclear, limiting targeted identification of stability determinants.
• What they did: The study built residue interaction networks for WT huPrP and mutants (Met166Val, Glu220Lys, Glu200Lys, Asp178Asn, Ser170Asn) using centrality, SPAF, and differential networks, then validated C-terminal (121–230) substitutions with CD thermal denaturation and MD.
• The result: Met213Ala significantly lowers melting temperature (Tm) versus WT, Val210Ala shows Tm comparable to WT, and MD increases average RMSD from 0.18 nm (WT) to 0.32 nm (Cys214Ala), 0.29 nm (Met206Ala), and 0.25 nm (Val210Lys).