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A molecular model of the amyloid fibril
C C Blake1, L C Serpell, M Sunde
1Laboratory of Molecular Biophysics, University of Oxford, UK.
Abstract:
We have investigated the ultrastructure of the homozygous amyloid fibrils from the vitreous humour of patients with Met30 familial amyloidotic polyneuropathy (FAP) by high-resolution electron microscopy and X-ray diffraction using synchrotron radiation. Image reconstruction of thin sections of Met30 FAP fibrils shows that they are composed of four parallel protofilaments, 50-60 A in diameter, arranged in a square around a hollow centre. The X-ray diffraction patterns are consistent with the presence in the protofilaments of a repeating unit of 24 beta-strands forming a continuous beta-sheet extended along the fibre axis, with the beta-strands perpendicular to the axis. We have characterized this repeat unit as one turn of a beta-sheet helix. This newly-described helix reconciles the classical cross-beta structure of amyloid with the twisted beta-sheet that is known to be the most stable form of the structure. All four beta-sheets composing the protofilament twist around a single helical axis which is coincident with the axis of the protofilament. Other amyloid diffraction patterns are similar to that of FAP, suggesting that the beta-sheet helix may be the generic core structure of amyloid.
Insights
Researchers studied amyloid fibrils in Met30 familial amyloidotic polyneuropathy (FAP) patients. They discovered a novel beta-sheet helix structure, potentially common to all amyloid fibrils.
Area of Science:
- Biophysics
- Structural Biology
- Materials Science
Background:
- Amyloid fibrils are associated with various human diseases, including familial amyloidotic polyneuropathy (FAP).
- The precise ultrastructure of amyloid fibrils, particularly the arrangement of beta-strands, remains incompletely understood.
- Met30 FAP is a specific type of hereditary amyloidosis caused by a mutation in the transthyretin gene.
Purpose of the Study:
- To elucidate the detailed ultrastructure of amyloid fibrils from patients with Met30 FAP.
- To determine the arrangement and conformation of beta-strands within the amyloid protofilaments.
- To investigate if the observed fibril structure is a common feature of other amyloid types.
Main Methods:
- High-resolution electron microscopy (EM) for ultrastructural imaging.
- X-ray diffraction (XRD) using synchrotron radiation for structural analysis.
- Image reconstruction techniques applied to EM data.
Main Results:
- Met30 FAP fibrils are composed of four parallel protofilaments (50-60 Å diameter) arranged in a square around a hollow core.
- X-ray diffraction patterns indicate protofilaments contain repeating units of 24 beta-strands forming a continuous beta-sheet helix.
- This beta-sheet helix structure reconciles the classical cross-beta structure with stable, twisted beta-sheet conformations.
Conclusions:
- A novel beta-sheet helix structure has been characterized as the repeating unit within Met30 FAP amyloid protofilaments.
- This beta-sheet helix represents a stable conformation that integrates known amyloid structural features.
- The structural similarity of other amyloid diffraction patterns suggests the beta-sheet helix may be a generic core structure for amyloid fibrils.