Hammarström P, Wiseman RL, Powers ET, Kelly JW.
Prevention of transthyretin amyloid disease by changing protein misfolding energetics.
Science. 2003 Jan 31;299(5607):713-6.
PubMed.
What, you might ask, could the Enron collapse have to do with amyloid formation? The answer is, everything, in a sense. If one takes an otherwise stable corporation and begins executing business strategies that destabilize it, the financial condition of the company begins to suffer. At early stages, the damage can be repaired, the company saved. However, once a critical point has been reached, the whole fabric of the business unravels. In today’s Science, Hammarstrom et al. demonstrate that this phenomenon is at the "core" of the process of transthyretin (TTR) amyloid assembly. Through the work of the Kelly group and others, it has been known that amino acid substitutions in TTR, or environmental conditions, could destabilize the normal tetramer "fold" of TTR, leading to tetramer dissociation and monomer destabilization (unraveling). The conformationally altered monomer then could assemble to form amyloid. In a compelling set of experiments, Hammarstrom now shows how small-molecule amyloid inhibitors can stabilize TTR. In addition, they examine the effects of the Thr119Met mutant of TTR, which is more resistant to amyloidogenesis and can work in trans to protect native TTR from unravelling.
The key to understanding the mechanics of these phenomena is summarized in Figure 4, which shows classic reaction coordinate diagrams for the dissociation of the TTR tetramer to an unfolded monomeric state capable of accessing amyloid formation pathways. Binding of a small molecule inhibitor to the TTR tetramer stabilizes it (i.e., it increases the activation energy for the tetramer-monomer transition). Binding of two inhibitors increases the activation energy further. The Thr199Met amino acid substitution also leads to maintenance of the tetramer, but not by tetramer stabilization, per se. Rather, Met199 DEstabilizes the transition state between tetramer and the folded monomer (increases the activation energy for the transition), making it much less likely that tetramer dissociation will occur. Bottom line: If one can decrease the energy of the ground state (here, the TTR tetramer), or increase the energy of the transition state, then there is a good chance that amyloidogenic tranformation can be prevented. This strategy should be applicable universally, e.g., with Aβ, α-synuclein, prion, etc. If only Ken Lay had read up on his thermodynamics!
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David Geffen School of Medicine at UCLA
The Enron Collapse and Amyloid Formation
What, you might ask, could the Enron collapse have to do with amyloid formation? The answer is, everything, in a sense. If one takes an otherwise stable corporation and begins executing business strategies that destabilize it, the financial condition of the company begins to suffer. At early stages, the damage can be repaired, the company saved. However, once a critical point has been reached, the whole fabric of the business unravels. In today’s Science, Hammarstrom et al. demonstrate that this phenomenon is at the "core" of the process of transthyretin (TTR) amyloid assembly. Through the work of the Kelly group and others, it has been known that amino acid substitutions in TTR, or environmental conditions, could destabilize the normal tetramer "fold" of TTR, leading to tetramer dissociation and monomer destabilization (unraveling). The conformationally altered monomer then could assemble to form amyloid. In a compelling set of experiments, Hammarstrom now shows how small-molecule amyloid inhibitors can stabilize TTR. In addition, they examine the effects of the Thr119Met mutant of TTR, which is more resistant to amyloidogenesis and can work in trans to protect native TTR from unravelling.
The key to understanding the mechanics of these phenomena is summarized in Figure 4, which shows classic reaction coordinate diagrams for the dissociation of the TTR tetramer to an unfolded monomeric state capable of accessing amyloid formation pathways. Binding of a small molecule inhibitor to the TTR tetramer stabilizes it (i.e., it increases the activation energy for the tetramer-monomer transition). Binding of two inhibitors increases the activation energy further. The Thr199Met amino acid substitution also leads to maintenance of the tetramer, but not by tetramer stabilization, per se. Rather, Met199 DEstabilizes the transition state between tetramer and the folded monomer (increases the activation energy for the transition), making it much less likely that tetramer dissociation will occur. Bottom line: If one can decrease the energy of the ground state (here, the TTR tetramer), or increase the energy of the transition state, then there is a good chance that amyloidogenic tranformation can be prevented. This strategy should be applicable universally, e.g., with Aβ, α-synuclein, prion, etc. If only Ken Lay had read up on his thermodynamics!
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