Oxidative Medicine and Cellular Longevity / 2019 / Article / Fig 2

Review Article

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.