3A4E

Crystal structure of Human Transthyretin (E54G)

3A4E の概要

• エントリーDOI: 10.2210/pdb3a4e/pdb
• 関連するPDBエントリー: 3A4D 3A4F
• 分子名称: Transthyretin, GLYCEROL, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: beta barrel, amyloid, amyloidosis, disease mutation, gamma-carboxyglutamic acid, glycoprotein, hormone, neuropathy, retinol-binding, secreted, thyroid hormone, transport, vitamin a, transport protein, thyroxine
• 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: 27879.01

構造登録者

Miyata, M.,Sato, T.,Nakamura, T.,Ikemizu, S.,Yamagata, Y.,Kai, H. (登録日: 2009-07-06, 公開日: 2009-12-22, 最終更新日: 2023-11-01)

主引用文献

Miyata, M.,Sato, T.,Mizuguchi, M.,Nakamura, T.,Ikemizu, S.,Nabeshima, Y.,Susuki, S.,Suwa, Y.,Morioka, H.,Ando, Y.,Suico, M.A.,Shuto, T.,Koga, T.,Yamagata, Y.,Kai, H.
Role of the glutamic acid 54 residue in transthyretin stability and thyroxine binding
Biochemistry, 49:114-123, 2010

PubMed Abstract: Transthyretin (TTR) is a tetrameric protein associated with amyloidosis caused by tetramer dissociation and monomer misfolding. The structure of two TTR variants (E54G and E54K) with Glu54 point mutation that cause clinically aggressive amyloidosis remains unclear, although amyloidogenicity of artificial triple mutations (residues 53-55) in beta-strand D had been investigated. Here we first analyzed the crystal structures and biochemical and biophysical properties of E54G and E54K TTRs. The direction of the Lys15 side chain in E54K TTR and the surface electrostatic potential in the edge region in both variants were different from those of wild-type TTR. The presence of Lys54 leads to destabilization of tetramer structure due to enhanced electrostatic repulsion between Lys15 of two monomers. Consistent with structural data, the biochemical analyses demonstrated that E54G and E54K TTRs were more unstable than wild-type TTR. Furthermore, the entrance of the thyroxine (T(4)) binding pocket in TTR was markedly narrower in E54K TTR and wider in E54G TTR compared with wild-type TTR. The tetramer stabilization and amyloid fibril formation assays in the presence of T(4) showed lower tetramer stability and more fibril formation in E54K and E54G TTRs than in wild-type TTR, suggesting decreased T(4) binding to the TTR variants. These findings indicate that structural modification by Glu54 point mutation may sufficiently alter tetramer stability and T(4) binding.

PubMed: 19950966
DOI: 10.1021/bi901677z

実験手法

X-RAY DIFFRACTION (1.7 Å)