4MRC

Human Transthyretin Ser52Pro Mutant

4MRC の概要

• エントリーDOI: 10.2210/pdb4mrc/pdb
• 関連するPDBエントリー: 4MRB
• 分子名称: Transthyretin, CALCIUM ION (3 entities in total)
• 機能のキーワード: hormone transporter, thyroxine t4, transport protein
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Secreted: P02766
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 27540.85

構造登録者

Chen, W.J.,Wood, S.P. (登録日: 2013-09-17, 公開日: 2014-01-08, 最終更新日: 2024-02-28)

主引用文献

Mangione, P.P.,Porcari, R.,Gillmore, J.D.,Pucci, P.,Monti, M.,Porcari, M.,Giorgetti, S.,Marchese, L.,Raimondi, S.,Serpell, L.C.,Chen, W.,Relini, A.,Marcoux, J.,Clatworthy, I.R.,Taylor, G.W.,Tennent, G.A.,Robinson, C.V.,Hawkins, P.N.,Stoppini, M.,Wood, S.P.,Pepys, M.B.,Bellotti, V.
Proteolytic cleavage of Ser52Pro variant transthyretin triggers its amyloid fibrillogenesis.
Proc.Natl.Acad.Sci.USA, 111:1539-1544, 2014

PubMed Abstract: The Ser52Pro variant of transthyretin (TTR) produces aggressive, highly penetrant, autosomal-dominant systemic amyloidosis in persons heterozygous for the causative mutation. Together with a minor quantity of full-length wild-type and variant TTR, the main component of the ex vivo fibrils was the residue 49-127 fragment of the TTR variant, the portion of the TTR sequence that previously has been reported to be the principal constituent of type A, cardiac amyloid fibrils formed from wild-type TTR and other TTR variants [Bergstrom J, et al. (2005) J Pathol 206(2):224-232]. This specific truncation of Ser52Pro TTR was generated readily in vitro by limited proteolysis. In physiological conditions and under agitation the residue 49-127 proteolytic fragment rapidly and completely self-aggregates into typical amyloid fibrils. The remarkable susceptibility to such cleavage is likely caused by localized destabilization of the β-turn linking strands C and D caused by loss of the wild-type hydrogen-bonding network between the side chains of residues Ser52, Glu54, Ser50, and a water molecule, as revealed by the high-resolution crystallographic structure of Ser52Pro TTR. We thus provide a structural basis for the recently hypothesized, crucial pathogenic role of proteolytic cleavage in TTR amyloid fibrillogenesis. Binding of the natural ligands thyroxine or retinol-binding protein (RBP) by Ser52Pro variant TTR stabilizes the native tetrameric assembly, but neither protected the variant from proteolysis. However, binding of RBP, but not thyroxine, inhibited subsequent fibrillogenesis.

PubMed: 24474780
DOI: 10.1073/pnas.1317488111

実験手法

X-RAY DIFFRACTION (1.54 Å)