Structure-based analysis of A19D, a variant of transthyretin involved in familial amyloid cardiomyopathy
Ferreira, Priscila (Universidade Federal do Rio de Janeiro. Instituto de Bioquímica Médica)
Sant'Anna, Ricardo (Universidade Federal do Rio de Janeiro. Instituto de Bioquímica Médica)
Varejão, Nathalia (Universidade Federal do Rio de Janeiro. Instituto de Bioquímica Médica)
Lima, Cinthia (Universidade Federal do Rio de Janeiro. Instituto de Bioquímica Médica)
Novis, Shenia (Centro de Estudos de Paramiloidose Antônio Rodrigues de Mello)
Barbosa, Renata V. (Centro de Estudos de Paramiloidose Antônio Rodrigues de Mello)
Caldeira, Concy M. (SONDA. Universidade Federal do Rio de Janeiro)
Rumjanek, Franklin D. (Universidade Federal do Rio de Janeiro. Instituto de Bioquímica Médica)
Ventura, Salvador (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Cruz, Marcia W. (Centro de Estudos de Paramiloidose Antônio Rodrigues de Mello)
Foguel, Debora (Universidade Federal do Rio de Janeiro. Instituto de Bioquímica Médica)
Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular

Date:	2013
Abstract:	Transthyretin (TTR) is a tetrameric beta-sheet-rich protein. Its deposits have been implicated in four different amyloid diseases. Although aggregation of the wild-type sequence is responsible for the senile form of the disease, more than one hundred variants have been described thus far, most of which confer a more amyloidogenic character to TTR, mainly because they compromise the stability of the protein in relation to monomer formation, which upon misfolding is intrinsically aggregation-prone. We report the case of a Brazilian patient suffering from a severe cardiomyopathy who carries a rare mutation in exon 2 of the TTR gene that results in an Ala to Asp substitution at position 19 (A19D). The putative pathogenic mechanisms of this variant were analyzed in silico. We constructed a structural model for the A19D tetramer from which its thermodynamic stability was compared to that displayed by the V30M (more amyloidogenic than WT-TTR) and T119M (non-amyloidogenic) variants. The FoldX force field predicted that A19D and V30M are 10. 88 and 8. 07 kCal/mol less stable than the WT-TTR, while T119M is 5. 15 kCal/mol more stable, which is consistent with the aggregation propensities exhibited by these variants. We analyzed the step in which the tetramer-dimer-monomer-unfolded monomer equilibrium might contribute the most to the increased or decreased amyloidogenicity in each variant. Our results suggest that the concentration of four non-native negative charges occur inside thyroxine-binding channels, and the loss of contacts at both the tetrameric and dimeric interfaces would account for an overall decreased stability of the tetramer and the consequent enhanced amyloidogenicity of the A19D variant. As far as we know, this is the first description of a non-V30M mutation in Brazil. © 2013 Ferreira et al.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Dimers (Chemical physics) ; Thermodynamics ; Brazil ; Point mutation ; Mutation ; Substitution mutation ; Aspartic acid ; Polymerase chain reaction
Published in:	PloS one, Vol. 8, issue 12 (2013) , art. e82484, ISSN 1932-6203

DOI: 10.1371/journal.pone.0082484
PMID: 24358189

14 p, 2.4 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Biotecnologia i de Biomedicina (IBB)
Articles > Research articles
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