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Evidence for assembly of prions with left-handed beta-helices into trimers.

ABSTRACT: Studies using low-resolution fiber diffraction, electron microscopy, and atomic force microscopy on various amyloid fibrils indicate that the misfolded conformers must be modular, compact, and adopt a cross-beta structure. In an earlier study, we used electron crystallography to delineate molecular models of the N-terminally truncated, disease-causing isoform (PrP(Sc)) of the prion protein, designated PrP 27-30, which polymerizes into amyloid fibrils, but we were unable to choose between a trimeric or hexameric arrangement of right- or left-handed beta-helical models. From a study of 119 all-beta folds observed in globular proteins, we have now determined that, if PrP(Sc) follows a known protein fold, it adopts either a beta-sandwich or parallel beta-helical architecture. With increasing evidence arguing for a parallel beta-sheet organization in amyloids, we contend that the sequence of PrP is compatible with a parallel left-handed beta-helical fold. Left-handed beta-helices readily form trimers, providing a natural template for a trimeric model of PrP(Sc). This trimeric model accommodates the PrP sequence from residues 89-175 in a beta-helical conformation with the C terminus (residues 176-227), retaining the disulfide-linked alpha-helical conformation observed in the normal cellular isoform. In addition, the proposed model matches the structural constraints of the PrP 27-30 crystals, positioning residues 141-176 and the N-linked sugars appropriately. Our parallel left-handed beta-helical model provides a coherent framework that is consistent with many structural, biochemical, immunological, and propagation features of prions. Moreover, the parallel left-handed beta-helical model for PrP(Sc) may provide important clues to the structure of filaments found in some other neurodegenerative diseases.

SUBMITTER: Govaerts C

PROVIDER: S-EPMC420396 | biostudies-literature | 2004 Jun

REPOSITORIES: biostudies-literature

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Evidence for assembly of prions with left-handed beta-helices into trimers.

Govaerts Cédric C Wille Holger H Prusiner Stanley B SB Cohen Fred E FE

Proceedings of the National Academy of Sciences of the United States of America 20040521 22

Studies using low-resolution fiber diffraction, electron microscopy, and atomic force microscopy on various amyloid fibrils indicate that the misfolded conformers must be modular, compact, and adopt a cross-beta structure. In an earlier study, we used electron crystallography to delineate molecular models of the N-terminally truncated, disease-causing isoform (PrP(Sc)) of the prion protein, designated PrP 27-30, which polymerizes into amyloid fibrils, but we were unable to choose between a trime ...[more]

PMID: 15155909

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Project description:The purpose of this study was to examine performance advantages associated with batting stance, in the form of left- vs. right-handed dominant stance, and orthodox vs. reverse stance, of talented junior cricket batters within age-restricted competitions. Data were sourced from the national male younger age competition (YAC; Under-17; n = 237) and older age competition (OAC; Under-19; n = 302), as well as female YAC (Under-15; n = 234) and OAC (Under-18; n = 260) over a 4-year period. Left-hand dominant (LHD) batters were consistently overrepresented in the male YAC (Right: 69.2%; Left: 30.8%) and OAC (Right: 68.2%; Left: 31.8%) compared with the expected general population distribution. Male LHD batters exhibited a significantly (p < 0.05) higher batting aggregate (YAC: 116.82 ± 84.75 vs. 137.84 ± 89.74; OAC: 117.07 ± 89.00 vs. 146.28 ± 95.99), scored more runs (YAC: 19.65 ± 12.32 vs. 23.96 ± 14.71; OAC: 19.27 ± 12.61 vs. 23.98 ± 14.15), spent more time batting (YAC: 45.33 ± 25.89 min vs. 54.59 ± 28.62 min; OAC: 39.80 ± 21.79 min vs. 49.33 ± 27.41 min), and scored more boundary-4s per game (YAC: 1.83 ± 1.40 vs. 2.44 ± 1.87; OAC: 1.76 ± 1.32 vs. 2.19 ± 1.83), across both YAC and OAC groups with small effect sizes. No overrepresentation was present for either female group (YAC, Right: 88.5%/Left: 11.5%; OAC, Right: 90.0%/Left: 10.0%). Female LHD batters exhibited significantly higher batting aggregate (68.97 ± 53.17 vs. 102.96 ± 73.48), batting average (13.24 ± 10.88 vs. 17.75 ± 12.28), and spent more time batting per game (25.52 ± 15.08 vs. 37.75 ± 26.76 min), but only at the OAC level with small-moderate effects sizes. Finally, there were few performance advantages identified to batting with a reverse stance, with further work needed to clarify any potential biomechanical benefits. Team selection practices may exploit the left-handed advantage by over-selecting talented left-handed junior cricketers. Practical implications for coaches include creating practice environments that negate the negative frequency-dependent selection, such as providing more practice opportunities for their players against left-handed opponents.

Dataset Information

Evidence for assembly of prions with left-handed beta-helices into trimers.

Publications

Evidence for assembly of prions with left-handed beta-helices into trimers.

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