Amyloid fibril model

Blake CC, Serpell LC, Sunde M, Sandgren O, Lundgren E. A molecular model of the amyloid fibril. CIBA Found Symp 1996 199 6-15 discussion 15-21, 40-16. 

Naiki H, Nakakuki K. First-order kinetic model of Alzheimer s beta-amyloid fibril extension in vitro. Lab Invest 1996 74 374-383. 

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.

Frequency-selective REDOR (fsREDOR) is a very powerful technique developed for the study of 13C and 15N uniformly labeled peptides or proteins [92]. The basic idea of this technique is to combine REDOR and soft n pulses to recouple a selected 13C-15N dipole-dipole interaction in a multiple-spin system. Usually one could use Gaussian shaped pulses to achieve the required selective n inversions. Other band selective shaped pulses have been developed for a more uniform excitation profile [93]. In its original implementation, fsREDOR was used to extract the intemuclear distances of several model crystalline compounds [92], In the past few years, this technique has proven to be very useful for the study of amyloid fibrils as well. For the Ure2p10 39 fibril samples containing 13C and 15N uniformly... 

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. 

The model of amyloid fibril formation is a nucleation step followed by growth, where the nucleation mechanism dictates the concentration and time dependence of the aggregation (Harper and Lansbury, 1997 ... 

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. 

Sikorski, P., and Atkins, E. (2005). New model for crystalline polyglutamine assemblies and their connection with amyloid fibrils. Biomacromolecules 6, 425-432. 

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).

Fig. 3. A generalized model of amyloid fibril polymorphism based on the formation of straight or coiled fibrils composed of several 4- to 5-nm-wide protofibril subunits. Notice that the flat ribbons containing several protofibril strands may twist (Fig. 2F and G) and may ultimately form tubes (Bauer et al, 1995).

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,... 

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). 

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). 

The Refolding, Gain-of-Interaction, and Natively Disordered classes of fibril models are at least partly consistent with the common properties of amyloid and amyloid-like fibrils. We summarize consistencies, inconsistencies, and uncertainties linking model class and amyloid property in Table I. In the following paragraphs, we describe these properties and discuss the extent to which they may be explained by the various classes of models. 

Many amyloid fibrils seem to be made up of smaller protofilaments. Although the number of protofilaments per fibril varies, the protofilaments have a fairly consistent diameter of 30 A (Serpell et al., 2000b Shirahama and Cohen, 1967 Shirahama et al., 1973). For some proteins, for example TTR, the protofilament diameter matches that of the native protein, suggesting that a Gain-of-Interaction model is plausible (Serpell et al., 1995). For other proteins, for example the SH3 domain, the protofilament seems too small to accommodate the native protein structure, suggesting that a Refolding model is plausible (Jimenez et al., 1999). 

The extreme stability of amyloid and amyloid-like fibrils is difficult to understand in terms of the three classes of fibril models. For the Refolding models, it has been suggested that the amyloid conformation is a default conformation for a polypeptide chain (Dobson, 1999). However, these models do not give a clear indication of what types of interactions differ in the amyloid conformation versus the native conformation, and so it is unclear why the amyloid conformation should be more stable. Also, it seems that the elevated protein concentrations associated with fibril formation might disproportionately favor nonspecific aggregation of the destabilized intermediate over amyloid fibril formation. 

In this chapter, we present several examples of structural models for amyloid fibrils, which we group into general classes. None of these general model classes can completely explain the common properties of amyloid and amyloid-like fibrils however, the Gain-of-Interaction models with a cross-/ spine seem most consistent with what is known. These models combine the structural aspect of the cross-/ spine with the specificity of sequence-dependent interactions to explain the observed diffraction, stability, and self-only association of amyloid fibrils. It is also possible... 

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