Amyloid fibrils, conformational

Figure 14.7 Ribbon diagram of one subunit of the globular form of transthyretin. The p strands are labeled A to H from the amino end. Strands C and D are thought to be unfolded to produce the conformation that forms amyloid fibrils. (Adapted from C.C.F. Blake et al., /. Mol. Biol. 121 339-356, 1978.)...

Just like in coiled-coils, p-sheet secondary structure (Fig. 2) is ubiquitous in natural examples and in proteins and biomaterials. Alzheimer s disease is characterized by fibrillar amyloid plaques in the cerebral parenchyma. The insoluble amyloid fibrils are predominantly formed upon conformational switching of the 42 amino acid... 

In the search for fibril formation inhibitors, the self-association to form amyloid fibrils of the A(3 peptides containing 40 and 42 amino acids can be treated as a coupled protein folding and polymerization process passing through multiple intermediate peptide species. The in vitro challenge is (1) to identify the various conformational forms and... 

Peterson SA, Klabunde T, Lashuel HA, Purkey H, Sacchettini JC, Kelly JW. Inhibiting transthyretin conformation changes that lead to amyloid fibril formation. Proc Natl Acad Sci USA 1998 95 12956-12960. 

A recent NMR study of the structure and dynamics of two amyloido-genic variants of human lysozyme (Chamberlain et al., 2001) showed that, although one variant destabilized the /6-domain much more than the other, it had no greater propensity to form amyloid fibrils. It was concluded that the increased ability of the variants to access substantially unfolded conformations of the protein is the origin of their amy-loidogenicity. This appears to reinforce the conclusions from ROA that a destabilized a-domain is involved in fibril formation. 

The conformational plasticity supported by mobile regions within native proteins, partially denatured protein states such as molten globules, and natively unfolded proteins underlies many of the conformational (protein misfolding) diseases (Carrell and Lomas, 1997 Dobson et al., 2001). Many of these diseases involve amyloid fibril formation, as in amyloidosis from mutant human lysozymes, neurodegenerative diseases such as Parkinson s and Alzheimer s due to the hbrillogenic propensities of a -synuclein and tau, and the prion encephalopathies such as scrapie, BSE, and new variant Creutzfeldt-Jacob disease (CJD) where amyloid fibril formation is triggered by exposure to the amyloid form of the prion protein. In addition, aggregation of serine protease inhibitors such as a j-antitrypsin is responsible for diseases such as emphysema and cirrhosis. 

It has been suggested recently that PPII helix may be the killer conformation in such diseases (Blanch et al., 2000). This was prompted by the observation, described in Section III,B, of a positive band at 1318 cm-1, not present in the ROA spectrum of the native state, that dominates the ROA spectrum of a destabilized intermediate of human lysozyme (produced by heating to 57°C at pH 2.0) that forms prior to amyloid fibril formation. Elimination of water molecules between extended polypeptide chains with fully hydrated 0=0 and N—H groups to form... 

Uversky, V. N., and Fink, A. L. (2004). Conformational constraints for amyloid fibrillation The importance of being unfolded. Biochim. Biophys. Acta Proteins Proteomics 1698, 131-153. 

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. 

Antzutkin, O. N., Balbach, J. J., and Tycko, R. (2003). Site-specific identification of nonbeta-strand conformations in Alzheimer s beta-amyloid fibrils by solid-state NMR. Biophys.J. 84, 3326-3335. 

Bousset, L., Briki, F., Doucet, J., and Melki, R. (2003). The native-like conformation of Ure2p in fibrils assembled under physiologically relevant conditions switches to an amyloid-like conformation upon heat-treatment of the fibrils. /. Struct. Biol. 141, 132-142. 

Jones, E. M., and Surewicz, W. K. (2005). Fibril conformation as the basis of species- and strain-dependent seeding specificity of mammalian prion amyloids. Cell 121, 63-72. 

Jones, E. M., and Surewicz, W. K. (2005). Fibril conformation as the basis of species- and strain-dependent seeding specificity of mammalian prion amyloids. Cell 121, 63-72. Kad, N. M., Myers, S. L., Smith, D. P., Smith, D. A., Radford, S. E., and Thomson, N. H. (2003). Hierarchical assembly of beta2-microglobulin amyloid in vitro revealed by atomic force microscopy./. Mol. Biol. 330, 785-797. 

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. 

Fig. 15 Schematic drawing of the formation of amyloid fibrils, (a) Monomeric insulin having an a-helical conformation, (b) [i-sheet (arrows) rich oligomers are being formed, (c) Amyloid fibrils having a diameter around 10 nm are being formed, (d) Higher magnification of the intrinsic repetitive (S-pIcatcd sheet structure of the amyloid fibril. The pictures were taken by transmission electron microscopy (TEM)...

Nilsson KPR, Herland A, Hammarstrdm P, Inganas O (2005) Conjugated polyelectrolytes conformation-sensitive optical probes for detection of amyloid fibril formation. Biochemistry 44 3718-3724... 

Tau protein interacts with many other proteins that can contribute to abnormal fibrillogenesis. One example is a-synuclein, which induces fibrillization of tau. Coincubation of a-synnclein and tau synergistically promotes fibrillization of both proteins in vitro. Mice with a-synuclein mutation or a tau mutation exhibit filamen-tons inclusions of both proteins, which are abundant neuronal proteins that normally adopt an nnfolded conformation but polymerize into amyloid fibrils in... 

Zerovnik, E. 2002. Amyloid-fibril formation. Proposed mechanisms and relevance to conformational disease. Eur J Biochem. 269 3362-71. 

Structural perturbation or conformational change in the soluble protein is important for amyloid formation. The observation of an amyloidogenic intermediate of transthyretin (TTR) in acidic pH led to the hypothesis of conformational perturbation as a prerequisite for amyloid fibril formation [6]. 

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