Amyloid formation: an emulation of matrix protein assembly?

Abstract

Although more than 20 different proteins are now associated with the amyloidoses, the fibrils share many properties. Despite disparity in primary and tertiary structures of the subunit proteins, assembled fibrils exhibit similar morphology, binding of Congo red, interaction with Thioflavine T, formation of complexes with serum amyloid P component, apolipoprotein E, several glycosaminoglycans, the receptor for advanced glycation endproducts and cross-recognition by some monoclonal antibodies. Thus, it is probable that the mechanism of amyloid generation involves a generic process that can be evoked by most, if not all, proteins under conditions that degrade the native conformation. As suggested by others, the beta-helix or beta-roll conformation may be the unifying element of fibril conformations. Several proteins that have evolved to form physiologically useful amyloid-like fibrils, as well as some proteins associated with pathological amyloidoses, exhibit sequence repeat patterns that may facilitate beta-roll or beta-helix formation. Threading analyses of 2 natural amyloid-forming proteins, curli and human Pmel 17, indicate compatibility of their primary structures with both beta sandwich and beta-helix conformations, suggesting a possible innate conformational pliability. In addition, these results may suggest that the misfolded form of some proteins that are associated with conformational disease may be the native conformation of other proteins to which they are linked by evolution. Finally, since many matrix and structural proteins are known to incorporate numerous tandem repeat sequence elements, we propose that the mechanism of fibril formation is fundamentally related to a general protein assembly process that is integral to the generation of cells and tissues.