Amyloid plaques are one of the hallmarks of Alzheimer's disease and were first described almost one hundred years ago by Alois Alzheimer. Today, however, their formation is still something of a mystery. It has been suggested that amyloid β, the protein precursor to amyloid fibrils, undergoes partial denaturation forming a peptide that is "stickier" than the native molecule. These peptides can then bond together side-by-side into a long stable fibril. A similar model has been proposed for formation of fibrils comprising other amyloidogenic proteins including β2-microglobulin and transthyretin.
Though in their native states these amyloidogenic proteins have no common structure, they all form amyloid fibrils composed of extensive cross β fibers, suggesting that a common glue holds all these different fibrils together. Understanding the composition of this glue could help scientists devise a strategy to dissolve it, though to date, which parts of the native proteins contribute to the cross β structure remains uncertain.
In Monday's Nature Structural Biology online, papers from two independent labs describe efforts to determine which amino acids of fibrillary β2-microglobulin are the most structurally inert and therefore most likely to contribute to the glue holding these fibrils together.
Yuji Goto at the Institute for Protein Research, Osaka University, and colleagues allowed β2-microglobulin fibrils to equilibrate with a deuterated solution thus replacing protons with the heavier deuterons. Following equilibrium they measured the remaining protons, and thus the most inert amino acids, by NMR. Sheena Radford and colleagues at the University of Leeds also used NMR but in this case to probe the denaturing effects of urea on the fibrillary intermediate.
Both labs arrived at a similar conclusion. They found the N- and C-terminal ends of the molecule are relatively unstable but five of the seven β strands, which comprise the core of the molecule, are protected from the denaturing effects of urea and from proton-deuteron exchange. The results suggest that the hydrogen bond network in these fibrils is extensive, thus explaining the relative stability and resistance to proteolysis exhibited by amyloid, and why polar solvents, such as dimethylsulfoxide, can dissolve amyloid in vitro. It remains to be seen, however, whether dissolution of amyloid in vivo will be possible.—Tom Fagan
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- Hoshino M, Katou H, Hagihara Y, Hasegawa K, Naiki H, Goto Y. Mapping the core of the beta(2)-microglobulin amyloid fibril by H/D exchange. Nat Struct Biol. 2002 May;9(5):332-6. PubMed.
- McParland VJ, Kalverda AP, Homans SW, Radford SE. Structural properties of an amyloid precursor of beta(2)-microglobulin. Nat Struct Biol. 2002 May;9(5):326-31. PubMed.