Gain-of-interaction models

Fig. 2. Classes of structural models of amyloid-like fibrils. The Refolding models propose that a native protein (circle) partially or completely unfolds to attain a new fold (rectangle) in the fibril (stack of rectangles). In contrast, the Gain-of-Interaction models propose that only part of the native protein changes and takes on a new structure in the fibril. The remainder of the protein (partial circle) retains its native structure. The Natively Disordered models begin with disordered proteins or protein fragments, and these become ordered in the fibril. PolyQ refers to polyglutamine.

The Gain-of-Interaction model of fibril formation (Elam et al, 2003) proposes that a conformational change in a limited region of the native protein exposes a normally inaccessible interaction surface that drives fibril formation. In these models, the bulk of the protein retains its native... 

In summary, two different Gain-of-Interaction models have been proposed for the fibrillar structure of /12m. The cross-(3 spine model (Ivanova et al., 2004) proposes a core composed of C-terminal /1-hairpins, and the direct-stacking model (Benyamini et al., 2003) proposes a core of native-like /12m molecules with their N- and C-terminal strands displaced. 

Many amyloid fibrils seem to be made up of smaller protofilaments. Although the number of protofilaments per fibril varies, the protofilaments have a fairly consistent diameter of 30 A (Serpell et al., 2000b Shirahama and Cohen, 1967 Shirahama et al., 1973). For some proteins, for example TTR, the protofilament diameter matches that of the native protein, suggesting that a Gain-of-Interaction model is plausible (Serpell et al., 1995). For other proteins, for example the SH3 domain, the protofilament seems too small to accommodate the native protein structure, suggesting that a Refolding model is plausible (Jimenez et al., 1999). 

In this chapter, we present several examples of structural models for amyloid fibrils, which we group into general classes. None of these general model classes can completely explain the common properties of amyloid and amyloid-like fibrils however, the Gain-of-Interaction models with a cross-/ spine seem most consistent with what is known. These models combine the structural aspect of the cross-/ spine with the specificity of sequence-dependent interactions to explain the observed diffraction, stability, and self-only association of amyloid fibrils. It is also possible... 

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