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Article

A New Folding Kinetic Mechanism for Human Transthyretin and the Influence of the Amyloidogenic V30M Mutation

1
Chemistry Department and Coimbra Chemistry Centre, Faculty of Science and Technology, University of Coimbra, Coimbra 3004-535, Portugal
2
Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra 3004-504, Portugal
3
Health Research Unit, School of Health Sciences, Leiria 2411-901, Portugal
*
Author to whom correspondence should be addressed.
Academic Editor: Salvador Ventura
Int. J. Mol. Sci. 2016, 17(9), 1428; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17091428
Received: 27 June 2016 / Revised: 18 August 2016 / Accepted: 23 August 2016 / Published: 31 August 2016
(This article belongs to the Collection Protein Folding)
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. View Full-Text
Keywords: transthyretin; WT-TTR; V30M-TTR; folding kinetics; amyloid; FAP; ATTR transthyretin; WT-TTR; V30M-TTR; folding kinetics; amyloid; FAP; ATTR
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MDPI and ACS Style

Jesus, C.S.H.; Almeida, Z.L.; Vaz, D.C.; Faria, T.Q.; Brito, R.M.M. A New Folding Kinetic Mechanism for Human Transthyretin and the Influence of the Amyloidogenic V30M Mutation. Int. J. Mol. Sci. 2016, 17, 1428. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17091428

AMA Style

Jesus CSH, Almeida ZL, Vaz DC, Faria TQ, Brito RMM. A New Folding Kinetic Mechanism for Human Transthyretin and the Influence of the Amyloidogenic V30M Mutation. International Journal of Molecular Sciences. 2016; 17(9):1428. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17091428

Chicago/Turabian Style

Jesus, Catarina S.H., Zaida L. Almeida, Daniela C. Vaz, Tiago Q. Faria, and Rui M.M. Brito 2016. "A New Folding Kinetic Mechanism for Human Transthyretin and the Influence of the Amyloidogenic V30M Mutation" International Journal of Molecular Sciences 17, no. 9: 1428. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17091428

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