Cross-/! spine model

B. Type II—Cross-/ Spine Models GNNQQNY and /12-Microglobulin. .. 248... 

A cross-// spine structure consists of two or more flat or twisted //-sheets, composed of parallel (Nelson et al., 2005) or antiparallel (Makin et al., 2005) //-strands, in a cross-/ arrangement. The cross-/ spine model of fibril formation proposes that a short segment of the native protein changes conformation to form one or more //-strands of a cross-/ spine. The seven-residue peptide GNNQQNY, derived from the prion-determining domain... 

Fig. 15. Cartoon representation of the cross-/ spine model of HET-s fibrils, based on Fig. 2 of Ritter et al. (2005). The stretch of residues 218-289 is shown as the four central //-strands, //1-//4, plus the connecting loops. N- and C-termini are indicated.

A cross-jS spine model was proposed for the fibril structure of human /]2-microglobulin (h/]2m) (Ivanova et al., 2004). h/I2m is a 99-amino acid serum protein with a 7-stranded /(-sandwich fold (Fig. 10A Saper et al, 1991). In patients on long-term kidney dialysis, the protein is deposited as amyloid fibrils in the joints (Floege and Ehlerding, 1996 Koch, 1992). In vitro-formed fibrils of h/)2m give a cross-/] X-ray diffraction pattern (Ivanova et al., 2004 Smith et al., 200S). Several studies have shown that segments of h/]2m form amyloid-like fibrils on their own (Ivanova et al., 2003 Jones et al., 2003 Kozhukh et al, 2002). 

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. 

In vitro, fibril formation by several proteins displays an initial lag phase, followed by a rapid increase in aggregation (reviewed in Rochet and Lansbury, 2000). Introduction of fibrillar seeds eliminates the lag phase. These cooperative aggregation kinetics suggest that fibril formation begins with the formation of a nucleus and proceeds by fibril extension. The structure of the nucleus must therefore act as a template for the protein s conformation in the fibril. As the structural requirements for templating are unclear, it is difficult to assess the consistency of the model classes with this feature of fibril formation. We have described one possible templating mechanism for the cross-/ spine of GNNQQNY (Nelson et al., 2005). 

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... 

Spine models are appropriate for performing multimodal dynamic analysis on bridges and let the seismic forces resisted by each pier determined in a natural way in accordance with their relative stiffness. They may be employed for normal bridges, normal meaning more or less straight, low skew, narrow deck, and cross section with limited distortion, i.e., with rigid closely spaced transverse frames or crossbeams. 

---