prions, structure, infectivity and amyloid formation.

There is a commentary and paper in the Nature of 31st of May 2007 on prion of great interest..
Prions are proteins which form insoluble amyloid structures associated with neurodegenerative disorders in mammals. The intriguing place of prions is that they are proteins whose conformation and ability for amyloid formation is self-seeding) and thereby infectious. The conformatiorially converted prion state can be transmitted from cell to cell within or, in some cases, between organisms. Prions, too, can be either deadly or beneficial.
The ability of proteins to form P-.sheet-rich amvloids is associated not only with disease, but also with diverse normal biological functions, including cell adhesion , skin pigmentation, adaptation to environmental stresses and perhaps even long-term neuronal memory.
The first identified prion protein identified was PrP, whose conversion to the prion conformcr (PrPsc) is associated with .several fatal neuro-degenerative diseases. More recently, several prions in yeast and other fungi have been identified that are unrelated to PrP or one another-; some of these may have beneficial effects. The most well-studied is Sup35 , a translation-termination factor whose conversion to the prion state reduces its activity. This increases the read-through of stop codons, revealing hidden genetic variation and creating complex new phenotypes in a single step.
Sup35 prions show two of the properties of prion biology that were initially identified for mammalian PrP. First, both Sup35 and PrP can adopt not just one prion conformation, but several related yet structurally distinct conformations (known as strain.or variants). Each conformation self-perpetuates and gives a distinct biological phenotype. Second, the transmission of the prion state between proteins of different species is limited by a species barrier that can occasionally be crossed. In both yeast and mammals the ability to establish and overcome species barriers is, in some unknown way, related to the ability of prions to form distinct Strains.
The carboxy-terminal domain of Sup35 encodes the translation-termination function Whether Sup35 exists in either a prion or a non-prion state is controlled by the interplay of two other domains11”. The middle region (M) has a strong solubilising activity and is very rich in charged residues. The amino (N) terminus is readily forms the amyloid conformation and is of unusually low sequen ce complexity, composed primarily of glutamine, asparagine, glycine and tyrosine residues .
In its non-prion state NM is compact, but plastic , rapidly fluctuating through diverse conformations. The structure of NM in its prion state is of interest. It may be that two discrete regions of the N domain are in self-contact within NM; the region between them is sequestered from intermolecular contacts, whereas elements proximal and distal to the contacts are not part of the amyloid core. Cross-linking NM molecules at one of the intermolecular contacts, but not elsewhere, accelerates nucleation. Other evidence suggests that most residues of the N domain are in jntermolecular contact, stacking in-register on themselves.
Single substitution mutations in certain regions of the N terminus can have profound effects on many aspects of prion biology: they can inhibit replication, bias prion conversion towards the production of distinct strains, and increase or decrease the ability of prions to cross species barriers. Which suggests that precise features of amino acid sequence have critical roles in Sup35 prion biology. Remarkably, however, scrambling the sequence of X docs not prevent prion formation. NM prion formation maybe mainly dependent on the amino acid composition and largely independent of primary sequence.
The authors of this remarkable paper show that only a small subset of ScNM peptides capture the ScNM protein from solution. And this is sufficient to convert soluble proteins to the prion state.
The same sequence elements are responsible for the species seeding activity and formation of distinct prion strains.
Surewicz W 2007 discriminating taste of prions Nature 447, pp 541-2
Tesier PM and Lindquist S 2007 Prion recognition elements govern nucleation, strain recognition and species barrier 447, 556-561

Martin Eastwood
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