Amyloid fibers

Fibrous proteins can serve as structural materials for the same reason that other polymers do they are long-chain molecules. By cross-linking, interleaving and intertwining the proper combination of individual long-chain molecules, bulk properties are obtained that can serve many different functions. Fibrous proteins are usually divided in three different groups dependent on the secondary structure of the individual molecules coiled-coil a helices present in keratin and myosin, the triple helix in collagen, and P sheets in amyloid fibers and silks. 

Alzheimer s Disease. Figure 1 A(3 monomers can self-associate to form dimers, trimers and higher oligomers. Globular structures of synthetic A(342 are known as A(3-derived diffusible ligands (ADDLs) (3-12-mers of A(3). These structures are similar to the smallest protofibrils and represent the earliest macromolecular assembly of synthetic A(3. The characteristic amyloid fiber exhibits a high beta-sheet content and is derived in vitro by a nucleation-dependent self-association and an associated conformational transition from random to beta-sheet conformation of the A(3 molecule. Intermediate protofibrils in turn self-associate to form mature fibers. 

They have many of the morphological and ultrastructural characteristics of disease filaments [11, 12] (Fig. 45-5). Assembly is a nucleation-dependent process that occurs through its amino-terminal repeats. The carboxy-terminal region, in contrast, is inhibitory. Assembly is accompanied by the transition from random coil to a [3-pleated sheet. By electron diffraction, a-synuclein filaments show a conformation characteristic of amyloid fibers. Under the conditions of these experiments, P- and y-synucleins failed to assemble, consistent with their absence from the filamentous lesions of the human diseases. When incubated with a-synuclein, P- and y-synucleins inhibit the fibrillation of a-synuclein, suggesting that they may indirectly influence the pathogenesis of Lewy body diseases and multiple system atrophy. 

Kirschner, D. A., Abraham, C., and Selkoe, D. J. (1986). X-ray diffraction from intraneuronal paired helical filaments and extraneuronal amyloid fibers in Alzheimer disease indicates cross-beta conformation. Proc. Natl. Acad. Sci. USA 83, 503-507. 

Kishimoto, A., Hasegawa, K., Suzuki, H., Taguchi, H., Namba, K., and Yoshida, M. (2004). Beta-helix is a likely core structure of yeast prion Sup35 amyloid fibers. Biochem. Biophys. Res. Commun. 315, 739-745. 

Perutz, M. F., Finch, J. T., Berriman, J., and Lesk, A. (2002). Amyloid fibers are water-filled nanotubes. Proc. Natl. Acad. Sci. USA 99, 5591-5595. 

Scheibel, T., Kowal, A. S., Bloom, J. D., and Lindquist, S. L. (2001). Bidirectional amyloid fiber growth for a yeast prion determinant. Curr. Biol. 11, 366-369. 

Schlumpberger, M., Wille, H., Baldwin, M. A., Buder, D. A., Herskowitz, I., and Prusiner, S. B. (2000). The prion domain of yeast Ure2p induces autocatalytic formation of amyloid fibers by a recombinant fusion protein. Protein Sci. 9, 440-451. 

Scheibel T, Parthasarathy R, Sawicki G, Lin X-M, Jaeger H, Lindquist SL. Conducting nanowires built by controlled self-assembly of amyloid fibers and selective metal deposition. Proc Natl Acad Sci USA 2003 100 4527-4532. 

Amyloid Fibers in Disease Several small aromatic molecules, such as phenol red (used as a nontoxic drug model), have been shown to inhibit the formation of amyloid in laboratory model systems. A goal of the research on these small aromatic compounds is to find a drug that would efficiently inhibit the formation of amyloid in the brain in people with incipient Alzheimer s disease. 

NMR spectroscopy can detect the conformational dynamics, which are also referred to as conformational switching of RNA molecules that coexist in different stable states. Solid-state NMR spectroscopy investigates molecules as powders or crystals and has become a powerful tool for the investigation of membrane proteins and their complexes with small peptide agonists. In addition, protein amyloid fibers and polymers can be investigated. 

A particularly well studied example of functional amyloid is provided by Curli assembly (53). Curli amyloids are assembled by bacteria such as Escherichia coli and Salmonella. Once assembled on the extracellular surface, Curli amyloid fibers function as natural ceU adhesion molecules that link together bacterial cells into robust cellular networks of biofilms. Other examples of functional amyloids include the silk fibers observed commonly in spider webs the Chorion proteins of egg shells Factor XII, which is an activator of the hemostatic system and other naturally produced adhesives and materials (54). 

Figure 2.62 A structure of amyloid fibers. A detailed model for A fibrils deduced from solid-state NMR studies shows that protein aggregation is due to the formation of large parallel P sheets. [From A. T. Petkova. Y, Ishii. J. J. Balbach, O. N. Antzukin, R. D. Leapman. F. Delagio. and R. Tycko. Proc, Natl. Acad Sci. US. A. 99(2002) 16742-16747.]...

Kalastavadi T, Tme HL (2010) Analysis of the [/ V2+] prion reveals stability of amyloid fibers as the key determinant of yeast prion variant propagation. J Biol Chem 285 20748-20755... 

Fig. 4. Schematic diagram of Sup35. Sup35 can be divided into three regions N (aa 1-124), M (aa 125-254), and C (aa 255-685) (see text for details). Full-length protein can support viability, propagate [P S/+], and form amyloid fibers in vitro. The N region alone or in combination with M can propagate [PSP] and form fibers however, these regions cannot support viability in the absence of C.

A number of diseases involve deposition of a characteristic amyloid fiber. However, in each of these diseases, the amyloid is derived from a different protein that has changed its conformation (three-dimensional structure) to that of the amyloid repeated p-sheet structure. Once amyloid deposition begins, it seems to proceed rapidly, as if the fibril itself were promoting formation and deposition of more fibrils (a phenomenon called "seeding"). The different clinical presentations in each of these diseases results from differences in the function of the native protein and the site of amyloid deposition. 

Amy Lloyd. Amy Lloyd has AL amyloidosis, which is characterized by [ ) deposition of amyloid fibers derived principally from the variable region of... 

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