Abstract
Prion diseases are caused by the propagation of misfolded cellular prion proteins (PrPs). A completely prion disease-resistant genotype, V127M129, has been identified in Papua New Guinea and verified in transgenic mice. To disclose the structural basis of the disease-resistant effect of the G127V mutant, we determined and compared the structural and dynamic features of the G127V-mutated human PrP (residues 91–231) and the wild-type PrP in solution. HuPrP(G127V) contains α1, α2 and α3 helices and a stretch-strand (SS) pattern comprising residues Tyr128-Gly131 (SS1) and Val161-Arg164 (SS2), with extending atomic distances between the SS1 and SS2 strands, and a structural rearrangement of the Tyr128 side chain due to steric hindrance of the larger hydrophobic side chain of Val127. The extended α1 helix gets closer to the α2 and α3 helices. NMR dynamics analysis revealed that Tyr128, Gly131 and Tyr163 underwent significant conformational exchanges. Molecular dynamics simulations suggest that HuPrP(G127V) prevents the formation of stable β-sheets and dimers. Unique structural and dynamic features potentially inhibit the conformational conversion of the G127V mutant. This work is beneficial for understanding the molecular mechanisms underlying the complete resistance of the G127V mutant to prion disease and for developing new therapeutics for prion disease.
Highlights
Prion diseases, the notorious transmissible spongiform encephalopathies (TSEs), are infectious and fatal central nervous system (CNS) degenerative diseases in some mammals[1]
D178N/M129 associated with FFI5,7 and D178N/V129 related to fCJD5,7 showed different intermolecular tetramers in crystal structures[34], different dynamic features[43,44,48] and different rates of the conversion to amyloid fibrils which were larger than WT in vitro[39]
The well-dispersed 1H-15N HSQC spectra illustrate that both human prion protein (HuPrP)(G127V) and WT HuPrP adopt well-folded structures (Figs 1 and S1)
Summary
The notorious transmissible spongiform encephalopathies (TSEs), are infectious and fatal central nervous system (CNS) degenerative diseases in some mammals[1]. Prion diseases manifest as a variety of clinical symptoms: Creutzfeldt-Jakob diseases (CJD, including sporadic, iatrogenic, variant, and familial/genetic CJD)[2,3,4,5], Gerstmann-Sträussler-Scheinker syndrome (GSS)[2,6], fatal familial insomnia (FFI)[2,5,7] and Kuru[2,8,9] These diseases are caused by the propagation of the insoluble scrapie isoform of the prion protein (PrPSc), a β-sheet-rich form, which is originated from the normal cellular prion protein (PrPC) through conformational conversion and is resistant to proteinases[2,10,11]. The V210I mutant alters the geometry of the α2 and α3 helices[27,49], it is fully susceptible to gCJD50 Another frailly protective mutant against sCJD, HuPrP(E219K)[17,18,19], has a slightly altered 3D structure, changed backbone dynamics, and redistributed surface electrostatic potentials[23]. Whether or not the alterations in the geometric packing of the α helices or the surface electrostatic potentials resist disease requires further studies
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