Cavity filling mutations at the thyroxine-binding site dramatically increase transthyretin stability and prevent its aggregationres
Sant'Anna, Ricardo (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Almedia, Maria Rosario (Instituto de Investigação e Inovação em Saúde da Universidade do Porto)
Varejao, Nathalia (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Gallego Alonso, Pablo (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Esperante, Sebastián (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Ferreira, Priscilla (Instituto de Bioquímica Médica Leopoldo de Meis)
Pereira-Henriques, Alda (Instituto de Investigação e Inovação em Saúde da Universidade do Porto)
Palhano, Fernando L. (Instituto de Bioquímica Médica Leopoldo de Meis)
De Carvalho, Mamede (Department Neurosciences. Hospital de Santa Maria. CHLN)
Foguel, Debora (Instituto de Bioquímica Médica Leopoldo de Meis)
Reverter i Cendrós, David (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Saraiva, Maria Joao (Instituto de Investigação e Inovação em Saúde da Universidade do Porto)
Ventura, Salvador (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)

Data:	2017
Resum:	More than a hundred different Transthyretin (TTR) mutations are associated with fatal systemic amyloidoses. They destabilize the protein tetrameric structure and promote the extracellular deposition of TTR as pathological amyloid fibrils. So far, only mutations R104H and T119M have been shown to stabilize significantly TTR, acting as disease suppressors. We describe a novel A108V non-pathogenic mutation found in a Portuguese subject. This variant is more stable than wild type TTR both in vitro and in human plasma, a feature that prevents its aggregation. The crystal structure of A108V reveals that this stabilization comes from novel intra and inter subunit contacts involving the thyroxine (T 4) binding site. Exploiting this observation, we engineered a A108I mutation that fills the T 4 binding cavity, as evidenced in the crystal structure. This synthetic protein becomes one of the most stable TTR variants described so far, with potential application in gene and protein replacement therapies.
Ajuts:	Ministerio de Economía y Competitividad BFU2015-66417-P Ministerio de Economía y Competitividad BFU2013-44763-P
Nota:	Altres ajuts: SUDOE INTERREG IV B (SOE4/P1/E831 to S.V.) and FEDER funds through the Operational Competitiveness Programme - COMPETE [grant number FCOMP-01-0124-FEDER-022718 (PEST-c/SAU/LA0002/2011) FCT-FEDER forunit 4293 in partnership with PT2020].
Drets:	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.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Aged ; Alanine ; Amino Acid Substitution ; Amyloidosis ; Asymptomatic Diseases ; Binding Sites ; Crystallography, X-Ray ; Female ; Gene Expression ; Humans ; Isoleucine ; Models, Molecular ; Prealbumin ; Protein Binding ; Protein Conformation, alpha-Helical ; Protein Conformation, beta-Strand ; Protein Interaction Domains and Motifs ; Protein Multimerization ; Protein Stability ; Recombinant Proteins ; Thermodynamics ; Valine
Publicat a:	Scientific reports, Vol. 7 (2017) , art. 44709, ISSN 2045-2322

DOI: 10.1038/srep44709
PMID: 28338000

15 p, 3.9 MB

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