Hierarchical Organization in the Amyloid Core of Yeast Prion Protein Ure2

Ngo, Sam; Gu, Lin; Guo, Zhefeng

doi:10.1074/jbc.m111.269092

Cited by 30 publications

(49 citation statements)

References 58 publications

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“…These residues are scattered through the prion domain, and the result with the single Ala residue implies that the nearest neighbor distance measured was an intermolecular distance. This result was confirmed by solid-state NMR studies of full-length Ure2p labeled with Ile (three residues in the prion domain) (35) and by electron spin resonance (36).…”

Section: Significancesupporting

confidence: 65%

Locating folds of the in-register parallel β-sheet of the Sup35p prion domain infectious amyloid

Gorkovskiy¹,

Thurber

Tycko

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The [PSI+] prion is a self-propagating amyloid of the translation termination factor, Sup35p, of Saccharomyces cerevisiae. The N-terminal 253 residues (NM) of this 685-residue protein normally function in regulating mRNA turnover but spontaneously form infectious amyloid in vitro. We converted the three Ile residues in Sup35NM to Leu and then replaced 16 single residues with Ile, one by one, and prepared Ile-1-13 C amyloid of each mutant, seeding with amyloid formed by the reference sequence Sup35NM. Using solid-state NMR, we showed that 10 of the residues examined, including six between residues 30 and 90, showed the ∼0.5-nm distance between labels diagnostic of the in-register parallel amyloid architecture. The five scattered N domain residues with wider spacing may be in turns or loops; one is a control at the C terminus of M. All mutants, except Q56I, showed little or no [PSI+] transmission barrier from the reference sequence, suggesting that they could assume a similar amyloid architecture in vitro when seeded with filaments of reference sequence Sup35NM. Infection of yeast cells expressing the reference SUP35 gene sequence with amyloid of several mutants produced [PSI+] transfectants with similar efficiency as did reference sequence Sup35NM amyloid. Our work provides a stringent demonstration that the Sup35 prion domain has the folded inregister parallel β-sheet architecture and suggests common locations of the folds. This architecture naturally suggests a mechanism of inheritance of conformation, the central mystery of prions.[PSI+] prion | solid-state NMR | dipolar recoupling | amyloid | Sup35 P rions are infectious proteins, mostly self-propagating amyloids. Amyloid is a filamentous polymer, rich in β-sheet structure, in which the β-strands run perpendicular to the long axis of the filament and the hydrogen bonds joining β-strands to make a sheet are along the long axis of the filament. In mammals, prions are uniformly lethal diseases, caused by amyloid formation of the PrP protein. In yeast and fungi, prions are not uniformly fatal and have widely varying effects (reviewed in ref. 1). Perhaps the most remarkable feature of prions is that they have strains or variants, distinct self-propagating forms of the same protein, analogous to alleles of a gene, each relatively stably propagated. The existence of different self-propagating prion variants implies an array of self-propagating structures, each based on the same protein sequence. Because each prion variant is self-propagating, and each variant represents a different amyloid structure/ conformation, there must be some mechanism by which the protein can template its conformation. This mechanism must operate for each of the many conformations that are possible for a given prion.An amino acid residue in a β-sheet can have interactions in three dimensions (Fig. 1A): (a) along the peptide chain; (b) with the residues it faces within the β-sheet but perpendicular to the peptide chain, including the residues to which its main chain N-H and >C = O are hydrog...

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Section: Significancesupporting

confidence: 65%

Locating folds of the in-register parallel β-sheet of the Sup35p prion domain infectious amyloid

Gorkovskiy¹,

Thurber

Tycko

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…This distance, measured rather accurately using a dipolar recoupling solid-state NMR experiment, is consistently about 0.5 nm for labeled Sup35p, Ure2p, and Rnq1p, and dilution with unlabeled molecules shows that the nearest neighbor is on another molecule (4-6, 47, 116, 117). Confirmation of this result for Ure2p comes from analogous experiments using electron spin resonance instead of NMR (118). Such experiments also suggest the locations of some of the folds (119).…”

Section: Het-s Infectious Amyloid Is a ␤-Helixsupporting

confidence: 61%

Yeast Prions: Structure, Biology, and Prion-Handling Systems

Wickner

Shewmaker

Bateman

et al. 2015

Microbiol Mol Biol Rev

131

142

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SUMMARY A prion is an infectious protein horizontally transmitting a disease or trait without a required nucleic acid. Yeast and fungal prions are nonchromosomal genes composed of protein, generally an altered form of a protein that catalyzes the same alteration of the protein. Yeast prions are thus transmitted both vertically (as genes composed of protein) and horizontally (as infectious proteins, or prions). Formation of amyloids (linear ordered β-sheet-rich protein aggregates with β-strands perpendicular to the long axis of the filament) underlies most yeast and fungal prions, and a single prion protein can have any of several distinct self-propagating amyloid forms with different biological properties (prion variants). Here we review the mechanism of faithful templating of protein conformation, the biological roles of these prions, and their interactions with cellular chaperones, the Btn2 and Cur1 aggregate-handling systems, and other cellular factors governing prion generation and propagation. Human amyloidoses include the PrP-based prion conditions and many other, more common amyloid-based diseases, several of which show prion-like features. Yeast prions increasingly are serving as models for the understanding and treatment of many mammalian amyloidoses. Patients with different clinical pictures of the same amyloidosis may be the equivalent of yeasts with different prion variants.

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“…More support for the parallel in-register b-sheet model has recently appeared from a study of Ure2 prion domain fibers using site-directed spin labeling and electron paramagnetic resonance (Ngo et al 2011). This study also provides evidence that a portion of the b-sheet region is more solvent-protected than the rest, suggesting that the b-sheets are organized in inner and outer cores that may differ in different prion strains.…”

Section: Models Of Prion Structuresmentioning

confidence: 67%

Prions in Yeast

2012

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The concept of a prion as an infectious self-propagating protein isoform was initially proposed to explain certain mammalian diseases. It is now clear that yeast also has heritable elements transmitted via protein. Indeed, the "protein only" model of prion transmission was first proven using a yeast prion. Typically, known prions are ordered cross-b aggregates (amyloids). Recently, there has been an explosion in the number of recognized prions in yeast. Yeast continues to lead the way in understanding cellular control of prion propagation, prion structure, mechanisms of de novo prion formation, specificity of prion transmission, and the biological roles of prions. This review summarizes what has been learned from yeast prions.

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Hierarchical Organization in the Amyloid Core of Yeast Prion Protein Ure2

Cited by 30 publications

References 58 publications

Locating folds of the in-register parallel β-sheet of the Sup35p prion domain infectious amyloid

Locating folds of the in-register parallel β-sheet of the Sup35p prion domain infectious amyloid

Yeast Prions: Structure, Biology, and Prion-Handling Systems

Prions in Yeast

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