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amyloid fibrils

Wednesday 6 February 2008

Definition : Amyloid fibrils are insoluble protein aggregates that have been associated with a range of diseases including BSE, Alzheimer’s, Parkinson’s and Creutzfeldt-Jakob Disease (CJD). They are long ribbons of amyloid 10nm in diameter and >100nm in length. Most often observed in vitro.

The fibrils can be created in the laboratory from a range of different proteins and peptides. Whatever the starting protein, the same structure is always found at the core of the fibril.

Stacks of parallel peptide strands running perpendicular to the fibril axis hydrogen-bond to form extended beta-sheets (above, left). These then stack across the fibril axis, and then intertwine to fibrils a few nanometres in diameter, and up to several microns in length (above, right).

Amyloid fibrils are thought to be composed of an intramolecular beta-sheet core running perpendicular to the fibril axis (beta-fibrils). It has more recently been discovered that under a variety of solution conditions, most proteins can be made to form amyloid fibrils indistinguishable from that of disease proteins.

Amyloid fibrils have a straight unbranching appearance on electron microscopy and a characteristic cross beta-diffraction pattern. These have allowed the prediction that amyloid fibrils are formed by layered arrays of extended beta-sheets. The beta-sheets form regular helical twists along the length of the fibre.

An alternative model based on the polyglutamine expansion that underlies Huntington disease indicates that the glutamine repeats form a cylindrical sheet 31 Å in diameter and made up of beta-strands with 20 residues per helical turn.

Successive turns are linked by hydrogen bonds between both the main-chain and the side-chain amides. The side chains point alternately into and out of the cylinder and the centre of the narrow tube contains bound water molecules.

Pathology

There are at least 21 distinct human diseases that are associated with amyloid fibril formation. Significant advancements in research in the past five years have led to the discovery that the toxic species in the amyloid diseases may not be the fibrils themselves, but rather the pre-fibrillar aggregates.

Although early attention focused on the possible toxicity of the amyloid fibrils, it is now hypothesized that the early aggregates are the main toxic species in aggregates, underscoring the need to develop an understanding of the entire aggregation process, not simply the structure of the final amyloid fibril.

See also

- amyloidoses
- amyloidogenesis
- conformational diseases

References

- Lomas DA, Carrell RW. Serpinopathies and the conformational dementias. Nat Rev Genet. 2002 Oct ;3(10):759-68. PMID : 12360234

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