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A New Folding Kinetic Mechanism for Human Transthyretin and the Influence of the Amyloidogenic V30M Mutation
Publication . Jesus, Catarina S. H.; Almeida, Zaida L.; Vaz, Daniela C.; Faria, Tiago Q.; Brito, Rui M. M.
Protein aggregation into insoluble amyloid fibrils is the hallmark of several
neurodegenerative diseases, chief among them Alzheimer’s and Parkinson’s. Although caused
by different proteins, these pathologies share some basic molecular mechanisms with familial
amyloidotic polyneuropathy (FAP), a rare hereditary neuropathy caused by amyloid formation
and deposition by transthyretin (TTR) in the peripheral and autonomic nervous systems. Among the
amyloidogenic TTR mutations known, V30M-TTR is the most common in FAP. TTR amyloidogenesis
(ATTR) is triggered by tetramer dissociation, followed by partial unfolding and aggregation of the
low conformational stability monomers formed. Thus, tetramer dissociation kinetics, monomer
conformational stability and competition between refolding and aggregation pathways do play
a critical role in ATTR. Here, we propose a new model to analyze the refolding kinetics of WT-TTR
and V30M-TTR, showing that at pH and protein concentrations close to physiological, a two-step
mechanism with a unimolecular first step followed by a second-order second step adjusts well to the
experimental data. Interestingly, although sharing the same kinetic mechanism, V30M-TTR refolds at
a much slower rate than WT-TTR, a feature that may favor the formation of transient species leading
to kinetic partition into amyloidogenic pathways and, thus, significantly increasing the probability of
amyloid formation in vivo.
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Fundação para a Ciência e a Tecnologia
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5876
Número da atribuição
UID/QUI/00313/2013