correo-e: foguel@bioqmed.ufrj.br
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Conferencia
The dark side of protein folding: studies with amyloidogenic proteins
Resumen
The formation of amyloid aggregates is the hallmark of the
amyloidogenic diseases. Transthyretin (TTR) is involved in senile
systemic amyloidosis (wt) and familial amyloidotic polyneuropathy
(variants). Through the use of high hydrostatic pressure (HHP), we
compare the stability among wt TTR, two disease-associated mutations
(V30M and L55P) and a trans-suppressor mutation (T119M). Our data show
that the amyloidogenic conformation, easily populated in the
disease-associated variant L55P, can be induced after decompression,
rendering the wt protein highly amyloidogenic. After decompression,
the recovered wt structure has weaker subunit interactions (it forms
a looser tetramer called T4*) and its stability is similar to L55P.
The observed sequence of stability was: L55P < V30M < wt << T119M.
After a cycle of compression-decompression at 37 oC and pH 5.6,
TTR (wt and variants) undergoes aggregation very rapidly (~ 30 min).
This HHP protocol has allowed us to screen several anti-amyloidogenic
compounds, including the well-known NSAID. Although all amyloid fibrils
exhibit a common architecture (cross beta-sheet topology), we decided
to investigate whether they display differences in stability that
might be correlated with their primary sequences. Indeed, this was the
case for the fibrils composed by TTR or by alpha-synuclein, involved
in Parkinson disease. We have also shown that the fibrils and the
protofibrils have different stabilities. The relevance of these
differences in stability to pathogenesis will be discussed.
Supported by: CNPq; FAPERJ, CAPES