Amyloid fibrils assembly

IV. Depicting Intermediate Stages of Amyloid Fibril Assembly.. . 223... 

AMYLOID FIBRIL ASSEMBLY PATHWAYS AND CYTOTOXICITY MECHANISMS... 

In this chapter, we first describe amyloid fibril polymorphism as seen by EM. We then show how SFM was used to depict intermediate stages of amyloid fibril assembly. Finally, we discuss the putative mechanism that might explain the cytotoxicity induced by these assembly intermediates. 

Wetzel R. Kinetics and thermodynamics of amyloid fibril assembly. Acc. Chem. Res. 2006 39 671-679. 

Khurana, R., lonescu-Zanetti, C., Pope, M., Li, J., Nielson, L, Ramirez-Alvarado, M., Regan, L., Fink, A.L, and Carter, S.A. (2003) A general model for amyloid fibril assembly based on morphological studies using atomic force microscopy. Biophysical Journal, 85, 1135-1144. 

Reddy G, Straub E, Thtrumalai D (2010) Dry amyloid fibril assembly in a yeast prion peptide is mediated by long-lived stmctures containing water wires. Proc Natl Acad Sci USA 107 21459-21464... 

Figure 9.6. Structural models for complexes between Cu(ll) and peptides derived from the A/3 peptide sequence, (a) Proposed model for Cu(ll) coordination with a peptide mode for which Cu(ll) binding inhibits fibril formation, (b) Crystal structure for a Cu(ll)-peptlde complex for which Cu(ll) binding promotes fibril formation, (c) Structural model for peptide arrangements in fibrils. With the exception of one histidine side chain, only the peptide backbone is shown. The Cu(ll) ions are depicted as small spheres. The dotted lines indicate hydrogen bonding between peptides arranged in a parallel fi-sheet. Adapted from Dong, J. Canfield, J. M. Mehta, A. K. Shakes, J. , Tian, B. Childers, W. S. Simmons, J. A. Mao, Z Scott, R. A. Warncke, K. Lynn, D. G. Engineering Metal Ion Coordination to Regulate Amyloid Fibril Assembly and Toxicity. Proceedings of the National Academy of Sciences of the United States of America 2007, 104, 13313-13318.

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... 

Van Nostrand WE, Melchor JP, Ruffini L. Pathologic amyloid beta-protein cell surface fibril assembly on cultured human cerebrovascular smooth muscle cells. J Neurochem 1998 70 216-223. 

From the Polymorphism of Amyloid Fibrils to Their Assembly Mechanism and Cytotoxicity... 

Inoue et al. (2003) found that silk proteins will form rodlike structures and that those structure will assemble into comblike or fabric-like superstructure. The scale differences between the rods (nanometers) and the superstructure (micrometers) would suggest that the rod formation is governed by amyloid fibril formation and that the supramolecular arrangement is governed by the properties of the rod (Oroudjev et al., 2002 Putthanarat et al., 2000), namely surface interaction and hydration. Three levels of association could be considered (i) within the proteins internal /1-strands will organize to form intra /1-sheet structures, (ii) /1-sheets from neighboring molecules will associate to form fibril subunits, and (iii) the fibril subunits will further associate to form larger fibrils or rods. 

Lazo, N. D., and Downing, D. T. (1998). Amyloid fibrils may be assembled from beta-helical protofibrils. Biochemistry 37, 1731-1735. 

Gilead, S., and Gazit, E. (2005). Self-organization of short peptide fragments From amyloid fibrils to nanoscale supramolecular assemblies. Supramol. Chem. 17, 87-92. 

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. 

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

FROM THE POLYMORPHISM OF AMYLOID FIBRILS TO THEIR ASSEMBLY MECHANISM AND CYTOTOXICITY... 

Unfortunately, the description of amyloid fibrils given above is simplistic since in vitro self-assembly of amyloid peptides and proteins yields polymorphic structures, as has been commonly observed in the past for other protein assemblies such as actin filaments (Millonig et al, 1988) and intermediate filaments (Herrmann and Aebi, 1999). On the one hand, assembly polymorphism complicates the characterization of fibril structure. On the other hand, it offers some insight into fibril formation. For this reason a more rational understanding of amyloid fibril formation at the molecular level is a key issue in the field of amyloidosis. 

These three examples emphasize the idea that a complete description of amyloid fibril polymorphisms will only be achieved when 3D structures at atomic detail become available (Luhrs et al., 2005). Last but not least, since the various morphologies observed for amyloid fibrils are defining the end point of the assembly process, an essential need is to properly define the early stages of fibril formation, namely the oligomeric states of the peptide or protein in solution prior to assembly into fibrils. 

Now that we have defined the starting point and the final products of the assembly process, the next step is to investigate the origin of amyloid fibril polymorphism through a detailed study of the assembly pathways... 

Amylin fibrils growing on mica were rather straight and exhibited various heights. They were compatible with the protofibril hypothesis of amyloid fibril polymorphism (Fig. 3), but no multistranded cables were present (Goldsbury et al, 1999). In contrast, coiled fibrils were often observed by SFM for fibrils assembled in solution prior to being adsorbed to mica (Jansen et al, 2005 Kad et al, 2003 Relini et al, 2004). In the case of... 

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