Transthyretin stability as a key factor in amyloidogenesis: X-ray analysisat atomic resolution

Citation
Mp. Sebastiao et al., Transthyretin stability as a key factor in amyloidogenesis: X-ray analysisat atomic resolution, J MOL BIOL, 306(4), 2001, pp. 733-744
Citations number
37
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Molecular Biology & Genetics
Journal title
JOURNAL OF MOLECULAR BIOLOGY
ISSN journal
0022-2836 → ACNP
Volume
306
Issue
4
Year of publication
2001
Pages
733 - 744
Database
ISI
SICI code
0022-2836(20010302)306:4<733:TSAAKF>2.0.ZU;2-9
Abstract
Transthyretin (TTR) amyloidosis is a conformational disturbance, which, Lik e other amyloidoses, represents a life threat. Here, we report a TTR varian t, TTR Thr119Met, that has been shown to have a protective role in the deve lopment of clinical symptoms in carriers of TTR Val30Met, one of the most f requent variants among TTR amyloidosis patients. In order to understand thi s effect, we have determined the structures of the TTR Val30Met/Thr119Met d ouble mutant isolated from the serum of one patient and of both the native and thyroxine complex of TTR Thr119Met. Major conclusions are: (i) new II-b onds within each monomer and monomer-monomer inter-subunit contacts, e.g. S er117-Ser117 and Met119-Tyr114, increase protein stability, possibly leadin g to the protective effect of the TTR Val30Met/Thr119Met variant when compa red to the single variant TTR Val30Met. (ii) The mutated residue (Met119) e xtends across the thyroxine binding channel inducing conformational changes that lead to closer contacts between different dimers within the tetramer. The data, at atomic resolution were essential to detect, for the first tim e, the subtle changes in the inter-subunit contacts of TTR, and explain the non-amyloidogenic potential of the TTR Thr119Met variant, improving consid erably current research on the TTR amyloid fibril formation pathway. (C) 20 01 Academic Press.