Amyloids: friend or foe?

Abstract

Amyloidogenesis is the aggregation of soluble proteins into structurally conserved fibers. Amyloid fibers are distinguished by their resistance to proteinase K, tinctorial properties and beta-sheet-rich secondary structure. Amyloid formation is a hallmark of many human diseases including Alzheimer's, Huntington's and the prion diseases. Therefore, understanding amyloidogenesis will provide insights into the development of therapeutics that target these debilitating diseases. A new class of ;functional' amyloids promises a unique glimpse at how nature has harnessed the amyloid fiber to accomplish important physiological tasks. Functional amyloids are produced by organisms spanning all aspects of cellular life. Herein we review amyloidogenesis, with special attention focused on the similarities and differences between the best characterized disease-associated amyloidogenic protein amyloid-beta and the formation of several functional amyloids. The implications of studying functional amyloidogenesis and the strategies organisms employ to limit exposure to toxic intermediates will also be discussed.

Fig. 1

Properties of amyloid polymerization. (A) Negatively stained electron micrograph of polymerized Aβ fibers. The scale bar represents 500 nanometers. (B) A graphic representation of amyloid fiber polymerization displaying nucleus dependent kinetics (blue line). Preformed amyloid fibers can act as seeds to speed the kinetics of fiber polymerization (red line). This process eliminates the lag phase associated with nucleus formation. (C) Model of amyloid fiber polymerization. A build up of monomer occurs which leads to the formation of multimers and finally the amyloid fiber end product. Large arrows represent processes that are energetically favorable while small arrows represent energetically unfavorable processes.

Fig. 2

Interaction between the curli subunit proteins CsgA and CsgB. (A) Negative stain electron micrograph of wild type cells producing curli. Scale bar represents 200 nanometers. (B) Model of Interbacterial Complementation. A donor cells secretes soluble CsgA that acts as a substrate for CsgB on an acceptor cells where curli biogenesis takes place. (C) A Congo red indicator plate demonstrating interbacterial complementation. The donor cells and the acceptor cells appear white until the two strains intersect. Once the two cell types intersect Congo red binding occurs demonstrating curli fiber polymerization as taken place. The arrow represents the direction in which the acceptor cells were streaked onto the plate. (D) The oligopeptide repeating units that compose the CsgA and CsgB proteins. The three dimensional structures of CsgA and CsgB are predicted to be composed of five imperfect β-strand-loop-β-strand oligopeptide repeats (R1–R5). Amino acids comprising the β-strand are located below the arrows, and amino acids predicted to comprise the loops are denoted with italicized blue letters. Bolded letters represent amino acids conserved in CsgB and CsgA at each position relative to the start of each repeating unit. Boxed letters represent amino acids conserved throughout the repeating units in both proteins.