The alpha sheet has been proposed as a possible intermediate state in the
conformational change in the formation of
amyloid fibrils by
peptides and proteins such as
amyloid beta,
poly-glutamine repeats,
lysozyme,
prion proteins, and
transthyretin repeats, all of which are associated with
protein misfolding disease. For example, amyloid beta is a major component of
amyloid plaques in the brains of
Alzheimer's disease patients, These proteins undergo a
conformational change from largely
random coil or
alpha helix structures to the highly ordered
beta sheet structures found in amyloid fibrils. Most beta sheets in known proteins are "twisted" about 15° for optimal hydrogen bonding and
steric packing; however, some evidence from
electron crystallography suggests that at least some amyloid fibrils contain "flat" sheets with only 1–2.5° of twist. An alpha-sheet amyloid intermediate is suggested to explain some anomalous features of the amyloid fibrillization process, such as the evident
amino acid sequence dependence of amyloidogenesis despite the belief that the amyloid fold is mainly stabilized by the
protein backbone. Xu, using atomic force microscopy, has shown that formation of amyloid fibers is a two-step process in which proteins first aggregate into colloidal spheres of ≈20 nm diameter. The spheres then join together spontaneously to form linear chains, which evolve into mature amyloid fibers. The formation of these linear chains appears to be driven by the development of an electrostatic dipole in each of the colloidal spheres strong enough to overcome coulomb repulsion. This suggests a possible mechanism by which alpha sheet may promote amyloid aggregation; the peptide bond has a relatively large intrinsic electrostatic dipole, but normally the dipoles of nearby bonds cancel each other out. In the alpha sheet, unlike other conformations, the peptide bonds are oriented in parallel so that the dipoles of the individual bonds can add up to create a strong overall electrostatic dipole. Notably, the protein
lysozyme is among the few native-state proteins shown to contain an alpha-strand region; lysozyme from both
chickens and
humans contains an alpha strand located close to the site of a
mutation known to cause
hereditary amyloidosis in humans, usually an
autosomal dominant genetic disease. A mechanism for direct alpha sheet and beta sheet interconversion has also been suggested, based on
peptide plane flipping in which the αRαL dipeptide inverts to produce a ββ dihedral angle conformation. This process has also been observed in simulations of transthyretin and implicated as occurring naturally in certain
protein families by examination of their dihedral angle conformations in crystal structures. It is suggested that alpha-sheet folds into multi-strand solenoids. Evidence employing retro-enantio N-methylated peptides, or those with alternating L and D amino acids, as inhibitors of beta-amyloid aggregation is consistent with alpha-sheet being the main material of the amyloid precursor. ==References==