Amyloid proteins amylin

The amyloidoses are a class of conformational diseases that arise from the conversion of normally unfolded or globular proteins into fibrillar aggregates that are either pathogenic or non-functional. At present there are more than 20 proteins that are associated with human amyloid diseases. This review focuses on three natively unfolded proteins that form fibrillar aggregates amyloid-, islet amyloid polypeptide ( amylin ), and a-synuclein, the diseases they contribute to and chemical and biophysical approaches that are used to investigate these proteins aggregation. 

Several pathological self-polymerizing systems have been biophysi-cally characterized sufficiently to permit identification of protein or peptide species that could serve as molecular targets in a structure-activity relationship. These include transthyretin (TTR) [73-76], serum amyloid A protein (SAA) [77], microtubule-associated protein tau [78-80], amylin or islet amyloid polypeptide (IAPP) [81,82], IgG light chain amyloidosis (AL) [83-85], polyglutamine diseases [9,86], a-synuclein [47,48] and the Alzheimer s (3 peptide [87-96]. A variety of A(3 peptide assay systems have been established at Parke-Davis to search for inhibitors of fibril formation that could be therapeutically useful [97]. 

The most detailed accounts of amyloid fibril polymorphism have come from EM studies of four different proteins or peptides, namely amyloid-/) (A/ l 4o or A/i v). transthyretin, calcitonin, and human amylin. The fibrils... 

Concerning the nature and structure of such amyloid peptide or protein channels, oligomers with annular morphologies have in fact been observed by EM for a-synuclein (Lashuel et al., 2002) and equine lysozyme (Malisauskas et al., 2003) even in the absence of any lipids or membranes. Channel-like structures have also been reconstituted in liposomes and observed by SFM for A/ i 4o, A/ j 42, human amylin, a-synuclein, ABri, ADan, and serum amyloid A (Fig. 5A Lin et al., 2001 Quist et al., 2005). Doughnut-shaped structures with a diameter of 10-12 nm and a central hole size of 1-2 nm (Fig. 5B) were imaged on top of lipid membranes (Quist et al., 2005). However, the radius of curvature of the SFM tips meant that it is not possible to say whether the pores were really traversing the lipid bilayer. 

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