Amyloid-type fibrils

Amyloid-type fibrils are linear polymers of about 3-10 nm width and range in length from hundreds of nanometres to micrometres (Fig. 2a) [23, 76]. Protein fibrils are... 

As a pharmaceutical product it is supplied as a lyophilized powder to be reconstituted with diluent for subcutaneous injection. The glucagon molecule possesses poor conformational stability and readily adopts conformers that result in extremely undesirable physical properties. It has been shown to form P-sheet aggregates and gels, including cytotoxic amyloid-type fibrils at high protein concentration under solution conditions similar to formulated conditions. 

In this model (Fay et al., 2005), portions of the N- and C-terminal regions, specifically residues 6 and 137, are in close proximity in the fibril, and the C-terminal domain retains a native-like structure. There is evidence that this non-amyloid-like fibril can convert to the cross-/ -containing filament with heat treatment, incubation at low pH (Bousset et al., 2003), or extensive drying (Fay et al., 2005), but it is unclear what sort of structural change might link the two fibril types. 

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. 

Peptides composed of various coded and noncoded amino acid residues self-assemble to form various types of supramolecular architectures, including supramolecular helices and sheets, nanotubes, nanorods, nanovesicles, and nanofibers. The higher-order self-assembly of supramolecular (3-sheets or supramolecular helices composed of short synthetic acyclic peptides leads to the formation of amyloid-like fibrils. Synthetic cyclic peptides were used in supramolecular chemistry as molecular scaffolding for artificial receptors, so as to host various chiral and achiral ions and other small neutral substrates. Cyclic peptides also self-assemble like their acyclic counterparts to form supramolecular structures, including hollow nanotubes. Self-assembling cyclic peptides can be served as artificial ion channels, and some of them exhibit potential antimicrobial activities against drug-resistant bacteria. 

Another prominent site of deposition of (5-amyloid fibrils with age and in AD is within the cerebrovasculature in areas of the brain prone to parenchymal amyloid deposition [137-139]. The peptide deposits along the surfaces of the smooth muscle cells of the vascular wall, resulting in the death of those cells and their replacement by amyloid fibrils, weakening the vascular wall. Endothelial cells are also affected [140]. The Dutch mutation in the APP precursor protein Q22E, within the (5-peptide sequence, produces a particularly fibrillogenic and toxic (to smooth muscle cells) peptide associated with primarily vascular deposition of mutant peptide and hemorrhagic vessel disease [137]. Thus, in addition to neuronal cells, the brain vascular smooth muscle cells are a pathologically relevant cell type. While the source of... 

Lashuel HA, Lai Z, Kelly JW. Characterization of the transthyretin acid denaturation pathways by analytical ultracentrifugation implications for wild-type, V30M, and L55P amyloid fibril formation. Biochemistry 1998 37 17851-17864. 

The 140-residue protein AS is able to form amyloid fibrils and as such is the main component of protein inclusions involved in Parkinson s disease. Full-length 13C/15N-labelled AS fibrils and AS reverse-labelled for two of the most abundant amino acids, K and V, were examined by homonuclear and heteronuclear 2D and 3D NMR.147 Two different types of fibrils display chemical shift differences of up to 13 ppm in the l5N dimension and up to 5 ppm for the backbone and side-chain 13C chemical shifts. Selection of regions with different mobility indicates the existence of monomers in the sample and allows the identification of mobile segments of the protein within the fibril in the presence of monomeric protein. At least 35 C-terminal residues are mobile and lack a defined secondary structure, whereas the N terminus is rigid starting from residue 22. In addition, temperature-dependent sensitivity enhancement is also noted for the AS fibrils due to both the CP efficiency and motional interference with proton decoupling.148... 

Human amylin, or islet amyloid polypeptide (hlAPP), is a 37-residue peptide hormone which forms both intracellular and extracellular (EC) amyloid deposits in the pancreas of most type II diabetic subjects. The core of the structure in the SDS micelle is an ot-helix that runs from about residues 5-28. Although the basic structural unit in the fibrils in... 

The forces that stabilize amyloid fibrils include specific hydrogen bonding, electrostatic interactions, n-n stacking, and hydrophobic interactions. Importantly, similar types of interactions stabilize the functional native structures of protein molecules (Anfinsen, 1973 Dill, 1990 Dobson and Karplus, 1999 Kauzmann, 1959). In this sense, the conditions that favor native protein folding might also be manipulated to facilitate the formation of amyloid fibrils. 

D domain swapping shares several features with amyloid fibril formation. It is specific in that only one type of protein is contained in any given... 

Each type of amyloid fibril is formed from one type of protein (Westermark et al., 2002), suggesting a specificity in fibril formation. This specific... 

Another approach toward fibrillar nanowires has been taken by Baldwin and colleagues (2006), who assembled a porphyrin binding protein onto the surface of an amyloid fibril. This binding protein could incorporate heme to form a functional b-type cytochrome. These fibrils could be developed to create wires for electron transfer, similar to structures observed in nature that consist of chains of heme molecules. 

Our findings reveal that amyloid fibrils represent a well-defined class of highly organised materials with similar physical properties that can be compared and contrasted on the nanometre scale with well-established types of more conventional materials [35]. Specifically, the core structure of the fibrils is stabilised primarily by interactions, particularly hydrogen bonds, involving the polypeptide main chain (Fig. 13.5). As the main chain is common to all... 

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