Amyloid fibril fibrils, structural models

Figure 19 Structural model of full-length HET-s. (A) Side view and (B) top view of 10 HET-s molecules within a HET-s amyloid fibril. Ellipsoids represent the N-terminal domains (residues 1-217) whose structure is not precisely known in this context. From Ref. 155 with permission.

Fig. 4. New structural models for amyloid and prion filaments with the parallel and in-register arrangement of //-strands in the //-sheets. //-Strands are denoted by arrows. The filaments are formed by hydrogen-bonded stacks of repetitive units. Axial projections of single repetitive units corresponding to each model are shown on the top. Lateral views of the overall structures are on the bottom. (A) The core of a //-helical model of the //-amyloid protofilament (Petkova et al., 2002). Two such protofilaments coil around one another to form a //-amyloid fibril. (B) The core of a //-helical model of the HET-s prion fibril (Ritter et al., 2005). The repetitive unit consists of two //-helical coils. (C) The core of a superpleated //-structura l model suggested for yeast prion Ure2p protofilaments and other amyloids (Kajava et al., 2004).

Kajava, A. V., Aebi, U., and Steven, A. C. (2005). The parallel superpleated beta-structure as a model for amyloid fibrils of human amylin. /. Mol. Biol. 348, 247-252. 

Petkova, A. T., Ishii, Y., Balbach, J. J., Antzutkin, O. N., Leapman, R. D., Delaglio, F., and Tycko, R. (2002). A structural model for Alzheimer s beta-amyloid fibrils based on experimental constraints from solid state NMR. Proc. Natl. Acad. Sci. USA 99, 16742-16747. 

Wang, J., Gulich, S., Bradford, C., Ramirez-Alvarado, M., and Regan, L. (2005). A twisted four-sheeted model for an amyloid fibril. Structure 13, 1279-1288. 

Protein structures are so diverse that it is sometimes difficult to assign them unambiguously to particular structural classes. Such borderline cases are, in fact, useful in that they mandate precise definition of the structural classes. In the present context, several proteins have been called //-helical although, in a strict sense, they do not fit the definitions of //-helices or //-solenoids. For example, Perutz et al. (2002) proposed a water-filled nanotube model for amyloid fibrils formed as polymers of the Asp2Glni5Lys2 peptide. This model has been called //-helical (Kishimoto et al., 2004 Merlino et al., 2006), but it differs from known //-helices in that (i) it has circular coils formed by uniform deformation of the peptide //-conformation with no turns or linear //-strands, as are usually observed in //-solenoids and (ii) it envisages a tubular structure with a water-filled axial lumen instead of the water-excluding core with tightly packed side chains that is characteristic of //-solenoids. 

Fig. 1. Structure of amyloid fibrils formed by the human amylin peptide. Negatively stained (A) and metal shadowed (B) fibrils formed by human amylin (adapted from Goldsbury et al., 2000a). (C) A human amylin fibril model formed by three protofibrils having a superpleated /i-structure (adapted from Kajava et al., 2005). Only Ca traces of the polypeptide chains are shown. (D) Atomic model of the cross-/ motif formed by the human amylin peptide (adapted from Kajava et al, 2005). Scale bar, 100 nm (A and B).

The resultant data have led to the proposal of numerous molecular models of amyloid fibril structure (Makin and Serpell, 2005). These models can be separated into three general classes (Fig. 2) (1) the Refolding models,... 

Fig. 2. Classes of structural models of amyloid-like fibrils. The Refolding models propose that a native protein (circle) partially or completely unfolds to attain a new fold (rectangle) in the fibril (stack of rectangles). In contrast, the Gain-of-Interaction models propose that only part of the native protein changes and takes on a new structure in the fibril. The remainder of the protein (partial circle) retains its native structure. The Natively Disordered models begin with disordered proteins or protein fragments, and these become ordered in the fibril. PolyQ refers to polyglutamine.

A prime example of a Refolding model is that of the insulin protofilament (Jimenez et al., 2002). Insulin is a polypeptide hormone composed of two peptide chains of mainly o -helical secondary structure (Fig. 3A Adams et al., 1969). Its chains (21- and 30-amino acids long) are held together by 3 disulfide bonds, 2 interchain and 1 intrachain (Sanger, 1959). These bonds remain intact in the insulin amyloid fibrils of patients with injection amyloidosis (Dische et al., 1988). Fourier transform infrared (FTIR) and circular dichroic (CD) spectroscopy indicate that a conversion to jS-structure accompanies insulin fibril formation (Bouchard et al., 2000). The fibrils also give a cross-jS diffraction pattern (Burke and Rougvie, 1972). 

Fig. 3. Refolding model of insulin protofilaments, from Jimenez et al. (2002). (A) Ribbon diagram of the crystal structure of porcine insulin (PDB ID code 3INS), generated with Pymol (DeLano, 2002). The two chains are shown as dark and light gray with N- and C-termini indicated. The dotted lines represent the three disulfide bonds 1 is the intrachain and 2 and 3 are the interchain bonds. (B) Cartoon representation of the structure of monomeric insulin in the fibril, as proposed by Jimenez et al. (2002). The thick, arrowed lines represent /1-strands, and thinner lines show the remaining sequence. The disulfide bonds are as represented in panel A, and N- and C-termini are indicated. (Components of this panel are not to scale.) (C) Cartoon representation of an insulin protofilament, showing a monomer inside. The monomers are proposed to stack with a slight twist to form two continuous /(-sheets. (Components of this panel, including the protofilament twist, are not to scale.) In the fibril cross sections presented byjimenez et al. (2002), two, four, or six protofilaments are proposed to associate to form the amyloid-like fibrils.

A cross-jS spine model was proposed for the fibril structure of human /]2-microglobulin (h/]2m) (Ivanova et al., 2004). h/I2m is a 99-amino acid serum protein with a 7-stranded /(-sandwich fold (Fig. 10A Saper et al, 1991). In patients on long-term kidney dialysis, the protein is deposited as amyloid fibrils in the joints (Floege and Ehlerding, 1996 Koch, 1992). In vitro-formed fibrils of h/)2m give a cross-/] X-ray diffraction pattern (Ivanova et al., 2004 Smith et al., 200S). Several studies have shown that segments of h/]2m form amyloid-like fibrils on their own (Ivanova et al., 2003 Jones et al., 2003 Kozhukh et al, 2002). 

C) Cross section of the Ure2p amyloid-like fibril model, showing the parallel superpleated -structure at the N-terminus, and various positions possibly occupied by the globular C-terminus (gray ovals). Panels B and C are based on Fig. 4 of Kajava et al. (2004). 

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