Figure 3–31 Detailed structure of the core of an amyloid fibril. Illustrated here is the cross-beta spine of the amyloid fibril that is formed by a peptide of seven amino acids from the protein Sup35, an extensively studied yeast prion. Consisting of the sequence glycine-asparagine-asparagine-glutamine-glutamine-asparaginetyrosine (GNNQQNY), its structure was determined by X-ray crystallography. Although the cross-beta spines of other amyloids are similar, being composed of two long β sheets held together by a “steric zipper,” different detailed structures are observed depending on the short peptide sequence involved. (A) One half  of the spine is illustrated. Here, a standard parallel β-sheet structure (see p. 116) is held together by a set of hydrogen bonds between two side chains plus hydrogen bonds between two backbone atoms, as illustrated (oxygen atoms red and nitrogen atoms blue). Note that in this example, the adjacent peptides are exactly in register. Although only five layers are shown (each layer depicted as an arrow), the actual structure would extend for many tens of thousands of layers in the plane of the paper. (B) The complete cross-beta spine. A second, identical β-sheet is paired with the first one to form a two-sheet motif that runs the entire length of the fibril. (C) View of the complete spine in (B) from the top. The closely interdigitated side chains form a tight, water-free junction known as a steric zipper. (Courtesy of David Eisenberg and Michael Sawaya, UCLA; based on R. Nelson et al., Nature 435:773–778, 2005. With permission from Macmillan Publishers Ltd.) tissue containing the protein aggregate. A set of closely related diseases—scrapie in sheep, Creutzfeldt–Jakob disease (CJD) in humans, Kuru in humans, and bovine spongiform encephalopathy (BSE) in cattle—are caused by a misfolded, aggregated form of a particular protein called PrP (for prion protein). PrP is normally located on the outer surface of the plasma membrane, most prominently in neurons, and it has the unfortunate property of forming amyloid fibrils that are “infectious” because they convert normally folded molecules of PrP to the same pathological form (Figure 3–33). This property creates a positive feedback loop that propagates the abnormal form of PrP, called PrP*, and allows the pathological conformation to spread rapidly from cell to cell in the brain, eventually causing death. It can be dangerous to eat the tissues of animals that contain PrP*, as witnessed by the spread of BSE (commonly referred to as “mad cow disease”) from cattle to humans. Fortunately, in the absence of PrP*, PrP is extraordinarily difficult to convert to its abnormal form.
A closely related “protein-only inheritance” has been observed in yeast cells. The ability to study infectious proteins in yeast has clarified another remarkable feature of prions. These protein molecules can form several distinctively different types of amyloid fibrils from the same polypeptide chain. Moreover, each type of aggregate can be infectious, forcing normal protein molecules to adopt the same type of abnormal structure. Thus, several different “strains” of infectious particles can arise from the same polypeptide chain.
Figure 3–32 The structure of an amyloid fibril. (A) Schematic diagram of the structure of a amyloid fibril that is formed by the aggregation of a protein. Only the cross-beta spine of an amyloid fibril resembles the structure shown in Figure 3–31. (B) A cut-away view of a structure proposed for the amyloid fibril that can be formed in a test tube by the enzyme ribonuclease A, illustrating how the core of the fibril—formed by a short segment— relates to the rest of the structure.
Electron micrograph of amyloid fibrils. (A, from L. Esposito, C. Pedone and
L.