Prion variants

Relationship Between Filament Polymorphism and Prion Variants 

A key feature of the protein-only hypothesis is that variants should represent distinct structural forms of the prion protein. A direct connection between filament structure and variants was made by Tanaka et al. (2004) using filaments made under different conditions (in this case, 4°C and 37°C). Filaments formed at 4°C were less stable against heating in 1.6% SDS and gave rise mostly to strong [PSI] variants after being transformed 

In Vitro Filament Populations Are Heterogeneous Whereas Intracellular Filament Populations Are Homogeneous 

As for /(-helical models in the context of prion variants, we note that /(-helices encompass quite a wide variety of cross-sectional shapes, each reflecting a different configuration of strands and turns in the coil (Hennetin et al., 2006 Kajava and Steven, 2006) thus it seems possible that different parts of the same prion domain could be assigned the role of coil-former and they would have different coil geometries whose distinctions could give rise to variant prions. However, we expect that variability of the /(-helices with more than one coil per subunit—already unlikely on other grounds, except for HET-s (Section VLB)—will be quite limited. 

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STRUCTURE, FUNCTION, AND AMYLOIDOGENESIS OF FUNGAL PRIONS FILAMENT POLYMORPHISM AND PRION VARIANTS... 

B. Relationship Between Filament Polymorphism and Prion Variants. .. 167... 

This model is a polar cross-/ structure with a left-handed twist that complies with the mass-per-unit-length data moreover, it readily accommodates sequence randomization because like residues are still stacked over like residues, regardless of their order, and sequence permutation does not increase the number of charged residues or prolines which would be most likely to destabilize structures of this kind (Fig. 10). The configuration of strands and turns allows some variation without putting charged residues inside the core structure. We envision that structural variations of this kind offer a plausible explanation for the phenomenon of prion variants, as discussed in Section VIII. 

Fig. 14. Prion variants may be propagated faithfully in vitro. (A) Scheme of propagation experiment. (B) Randomly selected transformants from experiments in which soluble Ure2p was seeded with extracts from [ure-o] cells or [URE3] variant one, two, or three cells, respectively. Panel (B) was adapted from Fig. 5 of Brachmann et al. (2005).

Baxa, U., Cassese, T., Kajava, A. V., and Steven, A. C. (2006). Structure, function, and amyloidogenesis of fungal prions Filament polymorphism and prion variants. Adv. Protein Chem. 73, 125-180. 

Shewmaker F, Kryndushkin D, Chen B, Tycko R, Wickner RB (2009) Two prion variants of Sup35p have in-register parallel beta-sheet structures, independent of hydration. Biochemistry 48 5074-5082... 

One remarkable property of yeast prions and their mammalian counterparts is the ability to take up several different yet stable [PRION+] forms that reflect different but stable conformational states of the prion protein. In the case of mammalian prions these are referred to as prion strains and can result in very distinct neuropathologies [94]. In yeast, however, to avoid confusion with the use of the term strain, which is typically used to describe different lineages of this organism, they are referred to as yeast prion variants . Like mammalian prion strains, yeast prion variants can give rise to variant-specific differences in the [PRION+] phenotypes. 

Variants have also been described for other native yeast prions [PIN1 [99] and [URE3] [103], as well as for chimeric prions comprising the Sup35 PrD from Saccharomyces species other than cerevisiae, fused to the S. cerevisiae C-terminal region [104,105]. As with the [/ S/+] variants, these other yeast prion variants show differences in the relative levels of soluble prion protein and in the stability of the prion during cell division. 

Kalastavadi T, Tme HL (2010) Analysis of the [/ V2+] prion reveals stability of amyloid fibers as the key determinant of yeast prion variant propagation. J Biol Chem 285 20748-20755... 

Shkundina IS, Kushnirov VV, Tuite MF, Ter-Avanesyan MD (2006) The role of the N-terminal oligopeptide repeats of the yeast Sup35 prion protein in propagation and transmission of prion variants. Genetics 172 827-835... 

Crist CG, Nakayashiki T, Kurahashi H, Nakamura Y (2003) PIII1 J, a novel Sup35-prion variant propagated with non-Gln/Asn oligopeptide repeats in the absence of the chaperone protein Hspl04. Genes Cells 8 603-618... 

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