Reference: Tompa P (2009) Structural disorder in amyloid fibrils: its implication in dynamic interactions of proteins. FEBS J 276(19):5406-15

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Abstract


Proteins are occasionally converted from their normal soluble state to highly ordered fibrillar aggregates (amyloids), which give rise to pathological conditions that range from neurodegenerative disorders to systemic amyloidoses. Recent methodological advances in solid-state NMR and EPR spectroscopy have enabled determination of the 3D structure of several amyloids at residue-level resolution. The general picture that emerges is that amyloids constitute parallel beta sheets, in which individual polypeptide chains run roughly perpendicular to the major axis of the fibril and are stacked in-register. Thus, the unifying theme of amyloid formation is the structural transition from an initial globular or intrinsically disordered state to a highly ordered regular form. In this minireview, we show that this description is somewhat oversimplified, because part of the polypeptide chain in the amyloid remains intrinsically disordered and does not become part of the ordered core. As demonstrated through examples such as the amyloids of alpha-synuclein and Abeta peptide and the yeast prions HET-s and Ure2p, these disordered segments are depleted in amino acids NQFYV and are enriched in DEKP. They are also significantly more charged and have a higher predicted disordered value than segments in the cross-beta core. We suggest that structural disorder in amyloid is a special case of 'fuzziness', i.e. disorder in the bound state that may serve different functions, such as the accommodation of destabilizing residues and the mediation of secondary interactions between protofibrils.

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Journal Article | Research Support, Non-U.S. Gov't | Review
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Tompa P
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