Prion fibrils

IV. Recent Advances in Structural Studies of Amyloid and Prion Fibrils. 10... 

Fig. 4. New structural models for amyloid and prion filaments with the parallel and in-register arrangement of //-strands in the //-sheets. //-Strands are denoted by arrows. The filaments are formed by hydrogen-bonded stacks of repetitive units. Axial projections of single repetitive units corresponding to each model are shown on the top. Lateral views of the overall structures are on the bottom. (A) The core of a //-helical model of the //-amyloid protofilament (Petkova et al., 2002). Two such protofilaments coil around one another to form a //-amyloid fibril. (B) The core of a //-helical model of the HET-s prion fibril (Ritter et al., 2005). The repetitive unit consists of two //-helical coils. (C) The core of a superpleated //-structura l model suggested for yeast prion Ure2p protofilaments and other amyloids (Kajava et al., 2004).

Sim VL, Caughey B (2009) Ultrastructures and strain comparison of under-glycosylated scrapie prion fibrils. Neurobiol Aging 30 2031-2042... 

In a third approach, Lindquist and her colleagues used fluorescent imaging and optical trapping techniques to analyze the forces which determine the integrity of yeast prion fibrils [56]. The results revealed strong non-covalent interactions that preserve the fibril structure even if individual fibrils unfold. 

Dong J, Castro CE, Boyce MC, Lang MJ, Lindquist S (2010) Optical trapping with high forces reveals unexpected behaviors of prion fibrils. Nat Struct Mol Biol 17 1422-1430... 

Another great achievement by SSNMR is the structure determination of the HET-s (218-289) fibril by the Meier group [42], as shown in Fig. 5. Total 90 and 44 H- H distance restraints obtained by the CHHC, NHHC and PDSD experiments, and 74 angle restraints obtained by TALOS [193], were used for structure calculations. The extraordinarily high order in the HET-s prion fibrils can be explained by the well-organized structure obtained by SSNMR. 

R. lycko and R. B. Wiekner, Molecular Structures of Amyloid and Prion Fibrils Consensus versus Controvert, Acc. Chem, Res., 2013, 46, 1487. 

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]. 

The contributions to this volume demonstrate that structural studies of fibrous /1-proteins, as well as prion and amyloid fibrils, have advanced rapidly thanks in large part to improved experimental techniques and better theoretical analysis of the ever-increasing structural data. It is also possible to learn from studies of naturally occurring silks (Dicko et al., this volume) howvariations in the conditions of production of silk threads from the same protein can produce a variety of /1-structures with very distinct... 

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. 

Filaments of full-length Ure2p are wider than prion domain filaments and they are not smooth-sided (Fig. 5) rather they have a backbone that closely resembles prion domain filaments in width, surrounded by globular domains—presumably, the G-terminal functional domains. This interpretation is supported by the results of protease digestion experiments that trim filaments of full-length Ure2p down to 4-nm core fibrils that closely resemble prion domain filaments assembled de novo (Fig. 5 Baxa et al, 2003). 

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