X‐ray diffraction and far‐UV CD studies of filaments formed by a leucine‐rich repeat peptide: structural similarity to the amyloid fibrils of prions and Alzheimer's disease β‐protein

Abstract

The development of neuro-degenerative diseases often involves amyloidosis, that is the formation of polymeric fibrillar structures from normal cellular proteins or peptides. For example, in Alzheimer's disease, a 42 amino acid peptide processed from the amyloid precursor protein forms filaments with a P-sheet structure. Because of this, the structure and dynamics of polymeric peptide filaments is of considerable interest. We showed previously that a 23 amino acid peptide constituting a single leucine-rich repeat (LRRN) polymerises spontaneously in solution to form long filaments of a P-sheet structure, a property similar to that of Alzheimer's P-amyloid and prion peptides. Here we report that a variant of LRRN in which a highly conserved asparagine residue is replaced by aspartic acid does not form either filaments or P structure. By contrast, a variant which replaces this asparagine residue with glutamine forms filaments ultrastructurally indistinguishable from those of LRRN. Electron micrographs of LRRN filaments show that many consist of two interleaved strands which appear to have a ribbon-like morphology. X-ray diffraction patterns from oriented LRRN fibres reveal that they are composed of long P-sheet arrays, with the interstrand hydrogen bonding parallel to the filament axis. This 'cross-P' structure is similar to that adopted by p-amyloid and prion derived fibres. Taken together, these results indicate that the LRR filaments are stabilised by inter-or intra-strand hydrogen bonded interactions comparable to the asparagine ladders of P-helix proteins or the 'glutamine zippers' of poly-glutamine peptides. We propose that similar stabilising interactions may underlie a number of characterised predispositions to neuro-degenerative diseases that are caused by mutations to amide residues. Our finding that amyloid-like filaments can form from a peptide motif not at present correlated with degenerative disease suggests that a propensity for Pfilament formation is a common feature of protein sub-domains.

Flexible docking of an amyloid‐forming peptide from β2‐microglobulin

“…This result makes physical sense and also emphasizes the importance of including multiple intermolecular interactions in the simulation. The 5th-lowest energy tetramer structure was shown to be structurally superimposible on a known b-helix fold, supporting earlier arguments that amyloid fibrils and b-helices are related [28][29][30]33]. Finally, the energy dependence on alcohol was consistent with a simple model in which the stability results from a cancellation of the polar and hydrophobic solvation terms, as proposed earlier [15].…”

Glycation Induces Formation of Amyloid Cross-β Structure in Albumin

“…Structural details obtained after these treatments have led to the idea that every polypeptide has the intrinsic propensity to adopt the cross-␤ structure tertiary/quarternary fold (42,(65)(66)(67)(68)(69)(70). We now show that glycation can induce refolding of albumin into cross-␤ structure conformation.…”

Amyloid aggregates of the prion peptide PrP106–126 are destabilised by oxidation and by the action of dendrimers

“…Other spontaneous modifications of the PrP106–126 peptide have been demonstrated, e.g., deamidation and isomerisation of N108 which occurs upon aging [35], but no biological or biophysical effects of such modifications were demonstrated. A similar modification was, however, enough to make a 23 amino acid leucine‐rich repeat peptide loose its ability to form β‐structure and to form fibrils [36].…”