Disruption of the X-loop turn of the prion protein linked to scrapie resistance

Scouras, Alexander D.; Daggett, Valerie
May 2012
PEDS: Protein Engineering, Design & Selection;May2012, Vol. 25 Issue 5, p243
Academic Journal
The prion diseases are a class of neurodegenerative diseases caused by the misfolding and aggregation of the prion protein (PrPC) into toxic and infectious oligomers (PrPSc). These oligomers are critical to understanding and combating these diseases. Differences in the sequence of PrP affect disease susceptibility, likely by shifting the tolerance of the protein for adaptation to PrPSc conformations and/or the recognition event between PrPSc and PrPC prior to conversion of the PrPC. We selected two sets of PrPSc-resistant mutant sequences for solvated atomistic molecular dynamics simulation to investigate the structural basis of resistance. The first group involved mutation in the X-loop (residues 164-171) resulting from selective breeding of sheep. The second group included eight mutants in mice identified by random mutagenesis targeting helix C followed by screening in cell cultures. Multiple simulations were performed of 14 different mutant and control constructs under different pH conditions for a total of 3.6 μs of simulation time. The X-loop formed a stable turn at neutral pH in wild-type PrP from both species. PrPSc-resistant mutations disrupted this turn even though only one of the mutants is in the X-loop. The X-loop is compact and buried in our previously described spiral models of PrPSc-like oligomers. On the basis of the findings presented here and in the context of the spiral oligomer model, we propose that expansion of the X-loop disrupts protofibril packing, providing a structural basis for resistance.


Related Articles

  • Recombinant Human Prion Protein Inhibits Prion Propagation in vitro. Jue Yuan; Yi-An Zhan; Abskharon, Romany; Xiangzhu Xiao; Martinez, Manuel Camacho; Xiaochen Zhou; Kneale, Geoff; Mikol, Jacqueline; Lehmann, Sylvain; Surewicz, Witold K.; Castilla, Joaquín; Steyaert, Jan; Shulin Zhang; Qingzhong Kong; Petersen, Robert B.; Wohlkonig, Alexandre; Wen-Quan Zou // Scientific Reports;10/9/2013, p1 

    Prion diseases are associated with the conformational conversion of the cellular prion protein (PrPC) into the pathological scrapie isoform (PrPSc) in the brain. Both the in vivo and in vitro conversion of PrPC into PrPSc is significantly inhibited by differences in amino acid sequence between...

  • Properties and Pathogenicity of Prion-Derived Peptides. Vassallo, Neville // Protein & Peptide Letters;Mar2009, Vol. 16 Issue 3, p230 

    Prion diseases are neurodegenerative disorders characterized by a hallmark event involving the posttranslational misfolding of the normal cellular prion protein (PrPC) into an infectious and toxic protease-resistant conformation (PrPSc). Studies on identification of the pathological prion...

  • RSARF: Prediction of Residue Solvent Accessibility from Protein Sequence Using Random Forest Method. Pugalenthi, Ganesan; Kandaswamy, Krishna Kumar; Kuo-Chen Chou; Vivekanandan, Saravanan; Kolatkar, Prasanna // Protein & Peptide Letters;Jan2012, Vol. 19 Issue 1, p50 

    Prediction of protein structure from its amino acid sequence is still a challenging problem. The complete physicochemical understanding of protein folding is essential for the accurate structure prediction. Knowledge of residue solvent accessibility gives useful insights into protein structure...

  • The induction of α-helical structure in partially unfolded HypF-N does not affect its aggregation propensity. Ahmad, B.; Vigliotta, I.; Tatini, F.; Campioni, S.; Mannini, B.; Winkelmann, J.; Tiribilli, B.; Chiti, F. // PEDS: Protein Engineering, Design & Selection;Jul2011, Vol. 24 Issue 7, p553 

    The conversion of proteins into structured fibrillar aggregates is a central problem in protein chemistry, biotechnology, biology and medicine. It is generally accepted that aggregation takes place from partially structured states of proteins. However, the role of the residual structure present...

  • Probing the Effect of Mutations on Cytochrome c Stability. Agueci, Francesco; Polticelli, Fabio; Sinibaldi, Federica; Cristina Piro, Maria; Santucci, Roberto; Fiorucci, Laura // Protein & Peptide Letters;Apr2007, Vol. 14 Issue 4, p335 

    Although the tertiary structures of mitochondrial cytochromes c (cyts c) seem to be remarkably similar, there are variations in their amino acid sequences, stability and functional properties. GdnHCl-induced unfolding experiments on engineered yeast and horse cyt c were carried out with the aim...

  • Dissection of Structure and Function of the N-Terminal Domain of Mouse DNMT1 Using Regional Frame-Shift Mutagenesis. D'Aiuto, Leonardo; Marzulli, Marco; Mohan, K. Naga; Borowczyk, Ewa; Saporiti, Federica; VanDemark, Andrew; Chaillet, J. Richard // PLoS ONE;2010, Vol. 5 Issue 3, p1 

    Deletion analysis of mouse DNMT1, the primary maintenance methyltransferase in mammals, showed that most of the Nterminal regulatory domain (amino acid residues 412-1112) is required for its enzymatic activity. Although analysis of deletion mutants helps to identify regions of a protein sequence...

  • Prion variants, species barriers, generation and propagation.  // Journal of Biology;2008, Vol. 8, p148 

    Prion variants faithfully propagate across species barriers, but if the barrier is too high, new variants (mutants) are selected, as shown in a recent BMC Biology report. Protein sequence alteration can prevent accurate structural templating at filament ends producing prion variants.

  • N-Terminal Helix-Cap in α-Helix 2 Modulates β-State Misfolding in Rabbit and Hamster Prion Proteins Sweeting, Braden; Brown, Eric; Khan, M. Qasim; Chakrabartty, Avijit; Pai, Emil F. // PLoS ONE;May2013, Vol. 8 Issue 5, p1 

    Susceptibility of a particular species to prion disease is affected by small differences in the sequence of PrP and correlates with the propensity of its PrP to assume the β-state. A helix-cap motif in the β2−α2-loop of native α-helical rabbit PrP, a resistant species, contains...

  • Finding the right fold. Goldenberg, David P. // Nature Structural Biology;Nov99, Vol. 6 Issue 11, p987 

    Using mutational analysis, three groups have compared the transition states for the folding of two pairs of homologous proteins. The results of these studies suggest that protein folding mechanisms are conserved and are defined primarily by the overall topology of the native structures, as...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics