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Oligomerization Profile of Human Transthyretin Variants with Distinct Amyloidogenicity
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Orientador(es)
Resumo(s)
One of the molecular hallmarks of amyloidoses is ordered protein aggregation
involving the initial formation of soluble protein oligomers that eventually grow into insoluble
fibrils. The identification and characterization of molecular species critical for amyloid fibril
formation and disease development have been the focus of intense analysis in the literature.
Here, using photo-induced cross-linking of unmodified proteins (PICUP), we studied the early stages
of oligomerization of human transthyretin (TTR), a plasma protein involved in amyloid diseases
(ATTR amyloidosis) with multiple clinical manifestations. Upon comparison, the oligomerization
processes of wild-type TTR (TTRwt) and several TTR variants (TTRV30M, TTRL55P, and TTRT119M)
clearly show distinct oligomerization kinetics for the amyloidogenic variants but a similar
oligomerization mechanism. The oligomerization kinetics of the TTR amyloidogenic variants
under analysis showed a good correlation with their amyloidogenic potential, with the most
amyloidogenic variants aggregating faster (TTRL55P > TTRV30M > TTRwt). Moreover, the early
stage oligomerization mechanism for these variants involves stepwise addition of monomeric units
to the growing oligomer. A completely different behavior was observed for the nonamyloidogenic
TTRT119M variant, which does not form oligomers in the same acidic conditions and even for longer
incubation times. Thorough characterization of the initial steps of TTR oligomerization is critical for
better understanding the origin of ATTR cytotoxicity and developing novel therapeutic strategies for
the treatment of ATTR amyloidosis.
Descrição
Palavras-chave
Transthyretin TTR TTR variants Amyloidosis ATTR Linear oligomerization Downhill polymerization Aggregation Amyloid
Contexto Educativo
Citação
Editora
MDPI