Amyloid fibrils stability

Wilkins DK, Dobson CM, Gross M (2000) Biophysical studies of the development of amyloid fibrils from a peptide fragment of cold shock protein B. Eur J Biochem 267 2609-2616 Williams AD, Shivaprasad S, Wetzel R (2006) Alanine scanning mutagenesis of Abeta(1 0) amyloid fibril stability. J Mol Biol 357 1283-1294... 

Makin OS, Atkins E, Sikorski P et al (2005) Molecular basis for amyloid fibril formation and stability. Proc Natl Acad Sci 102 315-320... 

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. 

Makin, O. S., Atkins, E., Sikorski, P., Johansson, J., and Serpell, L. C. (2005). Molecular basis for amyloid fibril formaUon and stability. Proc. Natl. Acad. Sci. USA 102, 315-320. 

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. 

Additional factors may influence fibril stability in vivo. The glycan molecules and amyloid P component found in amyloid deposits may stabilize amyloid fibrils (Pepys, 2006, and references therein). Also, monomer concentration is important to amyloid formation and stability in vivo several amyloidoses are associated with elevated levels of the fibril precursor protein, and deposits regress when the levels of the precursor protein are sufficiently reduced (Pepys, 2006, and references therein). 

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... 

Nilsson, M., Wang, X., Rodziewicz-Motowidlo, S., Janowski, R., Lindstrom, V., Onnerfjord, P., Westermark, G., Grzonka, Z., Jaskolski, M., and Grubb, A. (2004). Prevention of domain swapping inhibits dimerization and amyloid fibril formation of cystatin C Use of engineered disulfide bridges, antibodies, and carboxymethylpapain to stabilize the monomeric form of cystatin C.J. Biol. Chem. 279, 24236- 24245. 

In contrast, the two other amyloid diseases associated with TTR, familial amyloidotic polymeuropathy-l (FAP-1) and familial amyloidotic cardiomyopathy (FAC), are both autosomal dominant disorders (Table 1). The deposits of amyloid fibrils in these disorders form in tissues and organs and are made up of variant TTR, wt protein and TTR fragments. More than 80 TTR variants have been reported, with the majority of these being associated with disease (Hamilton and Benson 2001). These are single amino acid substitutions, with the exception of a Vall22 deletion mutation. It appears that certain amino acid substitutions decrease the stability of the tetramer and favour the formation of amyloidogenic intermediates that can then self-associate to form fibrils. FAR is usually fatal within 7 to 15 years after the appearance of symptoms. 

Fezoui Y, Teplow DB (2002) Kinetic smdies of amyloid beta-protein fibril assembly. Differential effects of alpha-helix stabilization. J Biol Chem 277 36948—36954 Fezoui Y, Hartley DM, Walsh DM, Selkoe DJ, Osterhout JJ, Teplow DB (2000) A de novo designed helix-turn-helix peptide forms nontoxic amyloid fibrils. Nat Struct Biol 7 1095-1099 Figueroa KP, Pulst SM (2003) Identification and expression of the gene for human ataxin-2-related protein on chromosome 16. Exp Neurol 184 669-678... 

Schmittschmitt JP, Scholtz JM (2003) The role of protein stability, solubility, and net charge in amyloid fibril formation. Protein Sci 12(10) 2374-2378... 

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