3TFB

Transthyretin natural mutant A25T

3TFB の概要

• エントリーDOI: 10.2210/pdb3tfb/pdb
• 分子名称: Transthyretin (2 entities in total)
• 機能のキーワード: transthyretin, immunoglobulin-like, transport protein, extracellular, hormone-binding protein, hormone binding 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: 25466.49

構造登録者

Azevedo, E.P.C.,Pereira, H.M.,Garratt, R.C.,Kelly, J.W.,Foguel, D.,Palhano, F.L. (登録日: 2011-08-15, 公開日: 2011-12-07, 最終更新日: 2023-09-13)

主引用文献

Azevedo, E.P.,Pereira, H.M.,Garratt, R.C.,Kelly, J.W.,Foguel, D.,Palhano, F.L.
Dissecting the Structure, Thermodynamic Stability, and Aggregation Properties of the A25T Transthyretin (A25T-TTR) Variant Involved in Leptomeningeal Amyloidosis: Identifying Protein Partners That Co-Aggregate during A25T-TTR Fibrillogenesis in Cerebrospinal Fluid.
Biochemistry, 50:11070-11083, 2011

PubMed Abstract: Deposition of amorphous aggregates and fibrils of transthyretin (TTR) in leptomeninges and subarachnoid vessels is a characteristic of leptomeningeal amyloidosis (LA), a currently untreatable cerebral angiopathy. Herein, we report the X-ray structure of the A25T homotetramer of TTR, a natural mutant described in a patient with LA. The structure of A25T-TTR is indistinguishable from that of wild-type TTR (wt-TTR), indicating that the difference in amyloidogenicity between A25T-TTR and wt-TTR cannot be ascribed to gross structural differences. Using pressure-induced dissociation of the tetramer, we show that A25T-TTR is 3 kcal/mol less stable than L55P-TTR, the most aggressive mutant of TTR described to date. After incubation for 15 days at 37 °C (pH 7.3), A25T-TTR forms mature amyloid fibrils. To mimic the environment in which TTR aggregates, we investigated aggregation in cerebrospinal fluid (CSF). Unlike L55P-TTR, A25T-TTR rapidly forms amyloid aggregates in CSF that incorporated several protein partners. Utilizing a proteomics methodology, we identified 19 proteins that copurified with A25T-TTR amyloid fibrils. We confirmed the presence of proteins previously identified to be associated with TTR aggregates in biopsies of TTR amyloidosis patients, such as clusterin, apolipoprotein E, and complement proteins. Moreover, we identified novel proteins, such as blood coagulation proteins. Overall, our results revealed the in vitro characterization of TTR aggregation in a biologically relevant environment, opening new avenues of investigation into the molecular mechanisms of LA.

PubMed: 22091638
DOI: 10.1021/bi201365r

実験手法

X-RAY DIFFRACTION (2.033 Å)