A model for the structure of the amyloid core fibril, based on the yeast prion protein Ure2p, as reported by Kajava et al in the May 25, 2004 issue of the Proceedings of the National Academy of Sciences of the USA (1) .
The atomic structure of the amyloid fibril is as yet undefined. Amyloid material from different sources exhibits common structural features, such as the presence of linear, unbranched, 4–13 nm diameter fibrils resistant to common denaturants and to proteolytic digestion. The fibril core shows a high content of β-structure, and x-ray fiber diffraction reveals a 4.7 Å ‘cross-beta’ structure; i.e., the β-strands run perpendicular to the fibril axis. Amyloid fibrils also show enhanced binding of certain fluorophores (thioflavin T) and dyes (Congo red); binding of the latter gives a characteristic yellow-green birefringence suggesting an ordered arrangement of dye molecules associated with the amyloid fibril, and often is used for diagnostic purposes in the clinical setting.
The model developed by Kajava et al (see their Figure 4) and shown here accommodates most of the known structural features of amyloid, and may represent a generic structure for most amyloids. The primary structure of yeast Ure2p shows three organizational regions: the N-terminal, prion-forming region, a ≈ 25-residue ‘linker’ region, and the C-terminal, biochemically-functional domain (shown in the figure in its folded, monomeric conformation). In this model, the amyloid core is formed exclusively from the prion domains, residues 1-65 in each Ure2p molecule (twelve Ure2p’s are shown), arranged to form a “parallel super-pleated β-structure” formed by “in-register stacking of serpentines, one per layer.” (12 such serpentines are represented in the figure, 6 blue and 6 yellow.) Thus, the fibril axis here is perpendicular to the plane of the page (i.e., the fibril is coming up out of the page), while the parallel β-sheets formed by successive layers of Ure2p prion domains are perpendicular to the fibril axis (parallel to the plane of the page).
The model by Kajava et al also allows for the observation that different amino acid sequences can form amyloid fibrils, because: …“regardless of sequence, like will stack over like.” And, for purposes of this course, the figure nicely illustrates two major structures formed by polypeptide chains: stable, fibril polymers, and folded, globular proteins. It remains for nature to determine when and where to utilize one or the other structure to fulfill its purposes. Therein lies the rub.
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2004 by the