3GRB

Crystal structure of the F87M/L110M mutant of human transthyretin at pH 6.5

3GRB の概要

• エントリーDOI: 10.2210/pdb3grb/pdb
• 関連するPDBエントリー: 1F41 1GKO 3DGD 3GPS 3grg
• 分子名称: Transthyretin, ZINC ION, GLYCEROL, ... (5 entities in total)
• 機能のキーワード: transthyretin, amyloid, amyloidosis, disease mutation, gamma-carboxyglutamic acid, glycoprotein, hormone, neuropathy, retinol-binding, secreted, thyroid hormone, transport, vitamin a, ligand binding protein, 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: 4
• 化学式量合計: 56901.51

構造登録者

Palmieri, L.C.,Freire, J.B.B.,Foguel, D.,Lima, L.M.T.R. (登録日: 2009-03-25, 公開日: 2010-04-07, 最終更新日: 2023-09-06)

主引用文献

Palmieri, L.de.C.,Lima, L.M.,Freire, J.B.,Bleicher, L.,Polikarpov, I.,Almeida, F.C.,Foguel, D.
Novel Zn2+-binding sites in human transthyretin: implications for amyloidogenesis and retinol-binding protein recognition.
J.Biol.Chem., 285:31731-31741, 2010

PubMed Abstract: Human transthyretin (TTR) is a homotetrameric protein involved in several amyloidoses. Zn(2+) enhances TTR aggregation in vitro, and is a component of ex vivo TTR amyloid fibrils. We report the first crystal structure of human TTR in complex with Zn(2+) at pH 4.6-7.5. All four structures reveal three tetra-coordinated Zn(2+)-binding sites (ZBS 1-3) per monomer, plus a fourth site (ZBS 4) involving amino acid residues from a symmetry-related tetramer that is not visible in solution by NMR. Zn(2+) binding perturbs loop E-α-helix-loop F, the region involved in holo-retinol-binding protein (holo-RBP) recognition, mainly at acidic pH; TTR affinity for holo-RBP decreases ∼5-fold in the presence of Zn(2+). Interestingly, this same region is disrupted in the crystal structure of the amyloidogenic intermediate of TTR formed at acidic pH in the absence of Zn(2+). HNCO and HNCA experiments performed in solution at pH 7.5 revealed that upon Zn(2+) binding, although the α-helix persists, there are perturbations in the resonances of the residues that flank this region, suggesting an increase in structural flexibility. While stability of the monomer of TTR decreases in the presence of Zn(2+), which is consistent with the tertiary structural perturbation provoked by Zn(2+) binding, tetramer stability is only marginally affected by Zn(2+). These data highlight structural and functional roles of Zn(2+) in TTR-related amyloidoses, as well as in holo-RBP recognition and vitamin A homeostasis.

PubMed: 20659897
DOI: 10.1074/jbc.M110.157206

実験手法

X-RAY DIFFRACTION (1.75 Å)