Fibril amyloid

The capability of imaging isolated biomolecules weakly bound to a substrate was shown by imaging GroEL molecules on mica with molecular-scale resolution. However, the resolution achieved in the imaging was on the order of nanometers. Thus, there was an interest in whether it is possible to obtain subnanometer resolution even on isolated biological molecules weakly bound to a substrate. 

To confirm this possibility, the author and coworkers imaged amyloid fibrils in buffer solution. Amyloid fibrils are formed from a variety of proteins, which are normally soluble in aqueous solution. Under certain conditions, the precursor proteins misfold to form 

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Shiv]i A P, Brown F, Davies M C, Jennings K H, Roberts C J, Tendler S J B, Wilkinson M J and Williams P M 1995 Scanning tunnelling microscopy studies of p-amyloid fibril structure and assembly FEBS Lett. 371 25-8... 

Amyloid fibrils are suggested to be built up from continuous P sheet helices... 

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.)...

Progress in deducing more structural details of these fibers has instead been achieved using NMR, electron microscopy and electron diffraction. These studies reveal that the fibers contain small microcrystals of ordered regions of the polypeptide chains interspersed in a matrix of less ordered or disordered regions of the chains (Eigure 14.9). The microcrystals comprise about 30% of the protein in the fibers, are arranged in p sheets, are 70 to 100 nanometers in size, and contain trace amounts of calcium ions. It is not yet established if the p sheets are planar or twisted as proposed for the amyloid fibril discussed in the previous section. 

Fibrous proteins are long-chain polymers that are used as structural materials. Most contain specific repetitive amino acid sequences and fall into one of three groups coiled-coil a helices as in keratin and myosin triple helices as in collagen and p sheets as in silk and amyloid fibrils. 

Blake, C., Serpell, L. Synchrotron x-ray studies suggest that the core of the transthyretin amyloid fibril is a continuous P sheet helix. Structure 4 989-998, 1996. 

Another pathway of influence in AD is the facilitation of amyloid- 3 (A 3) aggregation through an interaction with the PAS of AChE but not of BChE. Inversely, the usual BChE (and more specifically its C-terminus) was shown recently as to attenuate in vitro the formation of amyloid fibrils [4]. 

Diamant S, Podoly E, Friedler A et al (2006) Butyrylcho-linesterase attenuates amyloid fibril formation in vitro. Proc Natl Acad Sci USA 103(23) 8628-8633... 

Entry Peptide Xg X3 X4 Total charge at neutral pH Amyloid fibril formation... 

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... 

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

Slotta U, Hess S, Spiess K et al (2007) Spider silk and amyloid fibrils a structural comparison. Macromol Biosci 7 183-188... 

Figure 18.2 Production of senile plaque (S/A4 amyloid protein. Amyloid fS4 protein (/S/A4) is part of a 695, 751 or 770 amino-acid amyloid precursor protein APP. This is a transmembrane protein which is normally cleared within the fi/A4 amino acid sequence to give short 40 amino-acid soluble derivatives. It seems that under some circumstances as in Alzheimer s disease, APP is cleared either side of the fi/A4 sequence to release the 42/43 amino acid P/A4 which aggregates into the amyloid fibrils of a senile plaque (a). (See also Fig. 18.5.) Some factors, e.g. gene mutation, must stimulate this abnormal clearage leading to the deposition of P/A4 amyloid protein as plaques and tangles and the death of neurons (b)...

To this list of protein misfolding diseases can be added rare familial amyloidoses in which the mutated proteins have the classic amyloid fibril congophilic birefringence and cross-(3-sheet structure (Table 3). Many of these deposits have an impact on the central nervous system (TTR, cystatin, lysozyme) as well as on other organ systems. A newly described disease, familial British dementia, is associated with the deposition of Abri, a 34 amino acid, 4 kDa peptide cleaved from a 277 amino acid precursor sequence, the last 10 amino acids of which are not normally translated [52]. Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is... 

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... 

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... 

Han H, Weinreb PH, Lansbury PT Jr. The core Alzheimer s peptide NAC forms amyloid fibrils which seed and are seeded by beta-amyloid is NAC a common trigger or target in neurodegenerative disease Chem Biol 1995 2 163-169. 

Baures PW, Peterson SA, Kelly JW. Discovering transthyretin amyloid fibril inhibitors by limited screening. Bioorg Med Chem 1998 6 1389-1401. 

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. 

Oza VB, Petrassi HM, Purkey HE, Kelly JW. Synthesis and evaluation of anthranilic acid-based transthyretin amyloid fibril inhibitors. Bioorg Med Chem Lett 1999 9 1-6. 

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. 

Bonifacio MJ, Sakaki Y, Saraiva MJ. In vitro amyloid fibril formation from transthyretin the influence of ions and the amyloidogenicity of TTR variants. Biochim Biophys Acta 1996 1316 35 42. 

Jarrett JT, Lansbury PT Jr. Amyloid fibril formation requires a chemically discriminating nucleation event studies of an amyloidogenic sequence from the bacterial protein OsmB. Biochemistry 1992 31 12345-12352. 

LeVine H III. Screening for pharmacologic inhibitors of amyloid fibril formation. Methods Enzymol 1999 309 467 176. 

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. 

Sunde M, Blake C. The structure of amyloid fibrils by electron microscopy and X-ray diffraction. Adv. Protein Chem. 1997 50 123-159. 

Sunde M, Serpell LC, Bartlam M, Fraser PE, Pepys MB, Blake CC. Common core structure of amyloid fibrils by synchrotron X-ray diffraction. J Mol Biol 1997 273 729-739. 

Goldsbury C, Kistler J, Aebi U, Arvinte T, Cooper GJ. Watching amyloid fibrils grow by time-lapse atomic force microscopy. J Mol Biol 1999 285 33-39. 

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

Merlini G, Ascari E, Amboldi N, Bellotti V, Arbustini E, Perfetti V, Ferrari M, Zorzoli I, Marinone MG, Garini P, et al. Interaction of the anthracycline 4 -iodo-4 -deoxydoxorubicin with amyloid fibrils inhibition of amyloidogenesis. Proc Natl Acad Sci USA 1995 92 2959-2963. 

D. Protein Misfolding and Disease Amyloid Fibril Formation. 82... 

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. 

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