Human amylin fibrils

Fig. 1. Structure of amyloid fibrils formed by the human amylin peptide. Negatively stained (A) and metal shadowed (B) fibrils formed by human amylin (adapted from Goldsbury et al., 2000a). (C) A human amylin fibril model formed by three protofibrils having a superpleated /i-structure (adapted from Kajava et al., 2005). Only Ca traces of the polypeptide chains are shown. (D) Atomic model of the cross-/ motif formed by the human amylin peptide (adapted from Kajava et al, 2005). Scale bar, 100 nm (A and B).

Fig. 2. Electron micrographs highlighting the polymorphism of amyloid fibrils. (A) A single human calcitonin protofibril with a diameter of 4 nm (adapted from Bauer et al., 1995). (B) Different morphologies present in a transthyretin fibril preparation. Black arrowheads show oligomers of different sizes, the black arrow points to a 9- to 10-nm-wide fibril, and the white arrowhead marks an 4-nm-wide fibril (adapted from Cardoso et al., 2002). (C-F) Human amylin fibril ribbons (adapted from Goldsbury et al., 1997). (C) A single 5-nm-wide protofibril. (D-F) Ribbons containing two (D), three (E), or five (F) 5-nm-wide protofibrils. (G) A twisted ribbon made of four 5-nm-wide protofibril subunits of Api-40 (adapted from Goldsbury et al., 2000b). Scale bar, 50 nm (A-G).

Human amylin, or islet amyloid polypeptide (hlAPP), is a 37-residue peptide hormone which forms both intracellular and extracellular (EC) amyloid deposits in the pancreas of most type II diabetic subjects. The core of the structure in the SDS micelle is an ot-helix that runs from about residues 5-28. Although the basic structural unit in the fibrils in... 

Kajava, A. V., Aebi, U., and Steven, A. C. (2005). The parallel superpleated beta-structure as a model for amyloid fibrils of human amylin. /. Mol. Biol. 348, 247-252. 

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... 

For calcitonin, the thinnest single fibril, the protofibril, had a diameter of 4-5 nm and was observed at low (0.1-1 mM) calcitonin concentration (Fig. 2A Bauer et al, 1995). For transthyretin, short and flexible protofibrils 4—5 nm in diameter were observed, but the prominent species was an 8-nm diameter and up to 300-nm-long fibril (Fig. 2B Cardoso et al., 2002). For human amylin, 5-nm-wide protofibrils were rarely depicted by themselves (Fig. 2C), but they could be readily identified as a distinct building block of wider fibrils (Fig. 2D-F Goldsbury et al., 1997). The wider fibrils... 

For A/i it is worth noting that while single 5-nm protofibrils were rarely imaged by EM or SFM, the thinnest single fibrils had a diameter around 8-9 nm and were termed protofibrils by many researchers in the field (Goldsbury et al., 2005 Harper et al., 1997, 1999 Lambert et al, 1998 Nielsen et al., 1999 Walsh et al., 1997, 1999). Flat and twisted ribbons formed from 5-nm-wide subunits, as seen with human amylin, were also depicted for AjSi 4o (Fig- 2G Goldsbury et al., 2000b, 2005). 

A/1 it was possible to follow the growth of twisted ribbons, with a periodic twist of 80-130 nm, by depositing seeds on mica prior to the injection of a fresh peptide solution (Fig. 4C Goldsbury et al., 2005). In the case of human amylin, it was even possible to observe by time-lapse SFM how fibrils are formed from an oligomeric nucleus by initial growth in height from... 

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). 

Green, J. D., Goldsbury, C., Mini, T., Sundetji, S., Frey, P., Kisder, J., Cooper, G., and Aebi, U. (2003). Full-length rat amylin forms fibrils following substitution of single residues from human amylin./. Mol. Biol. 326, 1147-1156. 

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