Recent atomic models of amyloid fibril structure
Introduction
In 1935, the pioneering biophysicist Astbury [1] placed poached, stretched egg white in the X-ray beam and observed a diffraction pattern with perpendicular reflections at ∼4.7 Å along the meridional (stretched or fibril) direction and ∼10 Å along the equatorial direction. The pattern suggested that the protein chains of the egg white pack in an extended or β-conformation, with the chains perpendicular to the long (stretched) axis. Later, this cross-β X-ray diffraction pattern was observed for the elongated unbranched fibrils of amyloid deposits in diseased tissues [2]. More recently, the cross-β X-ray pattern was observed for numerous fibrils formed by removing non-pathological proteins from native conditions [3, 4, 5, 6]. Today, pathologists term those extracellular fibrils that are associated with disease as ‘amyloid’ and fibrils of normal proteins formed by changing solution conditions as ‘amyloid-like’ [7]. X-ray, electron microscopy (EM) and biochemical studies [2, 8, 9] have shown that amyloid and amyloid-like fibrils share common properties, including an elongated unbranched morphology, a substructure composed of multiple protofilaments and protofilament cores containing β-sheets with strands perpendicular to the long fibril axis. In this review, we focus on models of the arrangement of protein chains in the protofilament proposed from 1999 to 2005.
At present, no single model accounts adequately for all properties of all fibrils, but some models explain many properties of a range of different fibrils. The models discussed below are useful in coming to terms with fundamental questions about amyloid fibrils, such as do fibril-forming proteins exist in two distinctly different states (native and fibrillar); what is the nature of the conversion from native state to fibril; what is the structure of the common cross-β spine; is there an amino acid sequence signature for the formation of the cross-β spine; and what is the structural basis of the self-complementation of proteins?
Section snippets
Models of amyloid-like fibrils
A variety of atomic-level models have been proposed for amyloid fibrils [10, 11], with representatives shown in Figure 1, Figure 2 for each model class.
Conclusions
Recent progress in understanding amyloid structure includes the first atomic-level structures of the cross-β spine and the development of a range of models, using a wide variety of structural tools. These models are helpful in defining questions for the next stages of research. Important questions to answer include: what is the range of structures that form the cross-β spines of amyloid fibrils; to what extent do the remaining segments of the fibril-forming proteins retain their native
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
This article is based on work supported by the National Science Foundation under grant number 9904671 and the National Institutes of Health under grant GM0-31299. We thank MR Sawaya and S Sambashivan for discussions.
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