Prion protein fibrils

UV-Exposed Prion Protein Fibrils Show Altered Fibril Morphology... 

Smirnovas V, Kim J, Lu X et al (2009) Distinct structures of scrapie prion protein (PrPSc)-seeded versus spontaneous recombinant prion protein fibrils revealed by hydrogen/deuterium exchange. J Biol Chem 284 24233-24241... 

The conformational plasticity supported by mobile regions within native proteins, partially denatured protein states such as molten globules, and natively unfolded proteins underlies many of the conformational (protein misfolding) diseases (Carrell and Lomas, 1997 Dobson et al., 2001). Many of these diseases involve amyloid fibril formation, as in amyloidosis from mutant human lysozymes, neurodegenerative diseases such as Parkinson s and Alzheimer s due to the hbrillogenic propensities of a -synuclein and tau, and the prion encephalopathies such as scrapie, BSE, and new variant Creutzfeldt-Jacob disease (CJD) where amyloid fibril formation is triggered by exposure to the amyloid form of the prion protein. In addition, aggregation of serine protease inhibitors such as a j-antitrypsin is responsible for diseases such as emphysema and cirrhosis. 

Monte Carlo/simulated annealing (MC/SA) algorithm for sequential assignment in uniformly 13C, 15N-labeled proteins [137]. The two-dimensional (2D) NCACX and NCOCX spectra measured for the fibril samples of full-length Syrian hamster prion protein (residues 23-231) have been analyzed by the MC/SA protocol, from which it has been concluded that the fibril core is formed primarily in the region of residues 173-224 [54]. 

Baskakov, I. V., and Bocharova, O. V. (2005). In vitro conversion of mammalian prion protein into amyloid fibrils displays unusual features. Biochemistry 44, 2339-2348. 

Chan,J. C., Oyler, N. A., Yau, W. M., and Tycko, R. (2005). Parallel beta-sheets and polar zippers in amyloid fibrils formed by residues 10-39 of the yeast prion protein Ure2p. Biochemistry 44, 10669-10680. 

Bousset, L., Thomson, N. H., Radford, S. E., and Melki, R. (2002). The yeast prion Ure2p retains its native a-helical conformation upon assembly into protein fibrils in vitro. EMBOJ. 21, 2903-2911. 

Dos Reis, S., Coulary-Salin, B., Forge, V., Lascu, I., Begueret,J., and Saupe, S. J. (2002). The HET-s prion protein of the filamentous fungus Podospora anserina aggregates in vitro into amyloid-like fibrils. J. Biol. Chem. 277, 5703—5706. 

Fay, N., Inoue, Y., Bousset, L., Taguchi, H., and Melki, R. (2003). Assembly of the yeast prion Ure2p into protein fibrils. Thermodynamic and kinetic characterization. /. Biol. Chem. 278, 30199-30205. 

Diaz-Avalos, R., King, C. Y., Wall,J., Simon, M., and Caspar, D. L. (2005). Strain-specific morphologies of yeast prion amyloid fibrils. Proc. Natl. Acad. Sci. USA 102,10165-10170. Donne, D. G., Viles, J. H., Groth, D., Mehlhom, I., James, T. L., Cohen, F. E., Prusiner, S. B., Wright, P. E., and Dyson, H.J. (1997). Structure of the recombinant full-length hamster prion protein PrP(29-231) The N terminus is highly flexible. Proc. Natl. Acad. Sci. USA 94, 13452-13457. 

Warwicker, J. (2000). Modeling a prion protein dimer Predictions for fibril formation. 

The prion protein, implicated in diseases such as mad cow and Creutzfeldt-Jakob, is another that has been proposed to undergo extensive refolding to form fibrils. In its native, cellular conformation (PrPc), residues 23-124 are... 

It is common among fibril-forming proteins that a single protein can form fibrils of varied morphology. Variations may arise at the level of subunit conformation, which seems to be the case for the prion proteins, or at the level of protofilament packing, as described in the preceding for insulin. 

What is the nature of the insoluble forms of the prion protein They are hard to study because of the extreme insolubility, but the conversion of a helix to (3 sheet seems to be fundamental to the process and has been confirmed for the yeast prion by X-ray diffraction.11 It has been known since the 1950s that many soluble a-helix-rich proteins can be transformed easily into a fibrillar form in which the polypeptide chains are thought to form a P sheet. The chains are probably folded into hairpin loops that form an antiparallel P sheet (see Fig. 2-ll).ii-11 For example, by heating at pH 2 insulin can be converted to fibrils, whose polarized infrared spectrum (Fig. 23-3A) indicates a cross-P structure with strands lying perpendicular to the fibril axis >mm Many other proteins are also able to undergo similar transformation. Most biophysical evidence is consistent with the cross-P structure for the fibrils, which typically have diameters of 7-12 rnn."-11 These may be formed by association of thinner 2 to 5 nm fibrils.00 However, P-helical structures have been proposed for some amyloid fibrils 3 and polyproline II helices for others. 1 11... 

Surface assembly can also be used to orientate fibrils relative to the surface, generating fibrils that are horizontal or perpendicular to a surface. Zhang observed this behavior for the artificial GAV9 peptide which contains the consensus sequences from a-synuclein, A[3, and the prion protein (Zhang et al., 2006). This peptide assembles horizontally on HOPG surfaces and assembles perpendicular to the surface of mica. 

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