Polymorphism assembly

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

Inouye, H., and Kirschner, D. A. (2003). X-ray fibre diffraction analysis of assemblies formed by prion-related peptides Polymorphism of the heterodimer interface between PrPC and PrPSc. Fibre Diffract. Rev. 11, 102-112. 

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. 

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. 

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... 

In the case of human amylin and Afi our understanding of the diversity in amyloid fibril architecture is the result of a recursive process, since the early morphological observations were followed by assessment of the assembly pathway which in turn yielded a better understanding of fibril polymorphism. However, this structural knowledge is secondary compared to the discovery of small oligomers, globular oligomers, and early protofibrils that appear to be extremely cytotoxic (Hartley etal., 1999 Lambert et al, 1998 Walsh et al, 1999). 

Bauer, H. H., Aebi, U., Haner, M., Hermann, R., Muller, M., and Merkle, H. P. (1995). Architecture and polymorphism of fibrillar supramolecular assemblies produced by in vitro aggregation of human calcitonin./. Struct. Biol. 115, 1-15. 

Goldsbury, C., Frey, P., Olivieri, V., Aebi, U., and Muller, S. A. (2005). Multiple assembly pathways underlie amyloid-beta fibril polymorphisms./. Mol. Biol. 352, 282-298. 

Herrmann, H., and Aebi, U. (1999). Intermediate filament assembly Temperature sensitivity and polymorphism. Cell. Mol. Life Sd. 55, 1416-1431. 

Davey, R.J., Blagden, N., Righini, S., Alison, H., Quayle, M.J., Fuller, S., 2001, Crystal Polymorphism as a Probe for melecular Self-Assembly during Nucleation from Solutions The Case of 2,6-Dihydroxybenzoic Acid, Crystal Growth and Design, Vol. l,No. 2, 59-65. 

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