Amyloid peptide pores and the beta sheet conformation.

Over 20 clinical syndromes have been described as amyloid diseases. Pathologically, these illnesses are characterized by the deposition in various tissues of amorphous, Congo red stainingdeposits, referred to as amyloid. Under polarizing light microscopy, these deposits exhibit characteristic green birefringence. X-ray diffraction reveals cross-beta structure of extended amyloid fibrils. Although there is always a major protein in amyloid deposits, the predominant protein differs in each ofthe clinical syndromes. All the proteins exhibit the characteristic nonnative beta-sheet state. These proteins aggregate spontaneously into extended fibrils and precipitate out of solution. At least a dozen of these peptides have been demonstrated to be capable of channel formation in lipid bilayers and it has been proposed that this represents a pathogenic mechanism. Remarkably, the channels formed by these various peptides exhibit a number of common properties including irreversible, spontaneous insertion into membranes, production oflarge, heterogeneous single-channel conductances, relatively poor ion selectivity, inhibition of channel formation by Congo red and related dyes and blockade of inserted channels by zinc. In vivo amyloid peptides have been shown to disrupt intracellular calcium regulation, plasma membrane potential, mitochondrial membrane potential and function and long-term potentiation in neurons. Amyloid peptides also cause cytotoxicity. Formation of the beta sheet conformation from native protein structures can be induced by high protein concentrations, metal binding, acidic pH, amino acid mutation and interaction with lipid membranes. Most amyloid peptides interact strongly with membranes and this interaction is enhanced by conditions which favor beta-sheet formation. Formation of pores in these illnesses appears to be a spontaneous process and available evidence suggests several steps are critical. First, destabilization of the native structure and formation of the beta-sheet conformation must occur. This may occur in solution or may be facilitated by contact with lipid membranes. Oligomerization of the amyloid protein is then mediated by the beta strands. Amyloid monomers and extended fibrils appear to have little potential for toxicity whereas there is much evidence implicating amyloid oligomers of intermediate size in the pathogenesis of amyloid disease. Insertion of the oligomer appears to take place spontaneously although there may be a contribution of acidic pH and/or membrane potential. Very little is known about the structure of amyloid pores, but given that the amyloid peptides must acquire beta-sheet conformation to aggregate and polymerize, it has been hypothesized that amyloid pores may in fact be beta-sheet barrels similar to the pores formed by alpha-latrotoxin, Staphylococcal alpha-hemolysin, anthrax toxin and clostridial perfringolysin.