Alpha-2-Macroglobulin, a Hypochlorite-Regulated Chaperone and Immune System Modulator

Figure 2

Theoretical model showing the binding sites for monomeric Aβ on native α₂M and PZP. (a) The binding sites for monomeric Aβ (magenta; centred at amino acids 1314–1365 according to [21]) are normally concealed at the noncovalent interface of the (i) native α₂M tetramer. (ii) Binding to proteases (yellow triangles) results in the partial opening of the noncovalent interface between α₂M dimers and exposes the binding sites for monomeric Aβ on each subunit of transformed α₂M. (iii) The binding sites for monomeric Aβ are also exposed by hypochlorite-induced dissociation of the native α₂M tetramer into dimers. (iv) Native PZP (a disulfide-linked dimer) shares 82.7% sequence identity with α₂M in the Aβ binding region (magenta). The dimeric quaternary structure of native PZP results in surface exposure of the binding sites for monomeric Aβ. Although the binding sites for other misfolded proteins are not known, intuitively, they are also located at the normally buried hydrophobic interface of noncovalently associated α₂M dimers. (b) Image of the crystal structure of the transformed α₂M tetramer from PBD 4ACQ [3] with the binding sites for monomeric Aβ shown in magenta, which is comparable to the model shown in (a (ii)). The crystal structures of native α₂M or hypochlorite-modified α₂M dimers have not been solved.