Self-Perpetuating Structural States in Biology, Disease, and Genetics (2002) / Chapter Skim
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Sequence-dependent denaturation energetics: A major determinant in amyloid disease diversity
Sequence-dependent denaturation energetics: A major determinant in amyloid disease diversity
Pages 51-56
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From page 51... ...
The TTR missense mutations associated with familial amyloid disease display a wide range of diversity in age of disease onset, penetrance, etc. In diseases resembling and including the TTR amyloidoses, normally folded secreted proteins must first undergo partial denaturation to assemble into amyloid (7-10, 12~.
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From page 52... ...
Because the monomer unfolds five to six orders of magnitude faster than tetrameric TTR dissociates, the rate-determining dissociation step was measured by purposefully linking the quaternary structural changes to tertiary structural changes (measured by tryptophan fluorescence) mediated by urea concentrations in the unfolding posttransition region.
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From page 53... ...
Using urea concentrations in the posttransition region for tertiary structural changes directly links the slow TTR quaternary structural changes to the rapid tertiary structural changes and renders unfolding irreversible. Dissociation time courses for the TTR variants described above fit well to a single exponential over a range of urea concentrations.
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From page 54... ...
Fibril Formation Rates Are Predicted by Tetramer Dissociation Rates. TTR will form amyloid fibrils in vitro under partially denaturing conditions imposed by lowering either the pH (simulating the endocytic pathway)
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From page 55... ...
ARbougb tbermo~namic stab1hty dictates ~betber amyloid ~rmation is possible in a g~en denaturing environment, tbe rate at wbicb tbe tetramer d~sociates to tbe pardal~ un~lded monomeric a~loidogenic intermediate governs 1be rate of dbrd ~rmation and 1bere~re contributes sign1Ucant~ to disease severhy. L33P TTR e~bib~s severe patbology, because tbe tetramet botb dissociates rapidly and is bigb~ destabiDzed, explaining w~ tbis mutation con~rs 100~ disease penetrance witb tbe earhest age of dLease onset (15-23 years~ ~en tbougb tbe V30~ tetramer is dight~ more destabUized 1ban L35P, 1be dLcase pbenotype ~ milder because V30H dissociates even more dow~ 1ban ~VT.
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From page 56... ...
Despite significant effort, however, we have not been able to demonstrate intracellular TTR amyloidosis. The slow tetramer dissociation process required for amyloid fibril formation revealed within may provide some clues regarding how and where amyloidosis occurs in a human.
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