2G4G

Crystal structure of human transthyretin at pH 4.6

2G4G の概要

• エントリーDOI: 10.2210/pdb2g4g/pdb
• 関連するPDBエントリー: 1F41 2G3X 2G3Z 2G4E
• 分子名称: Transthyretin (2 entities in total)
• 機能のキーワード: ttr, amyloid fibrils formation, point mutations, 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: 27554.72

構造登録者

Pasquato, N.,Folli, C.,Berni, R.,Zanotti, G. (登録日: 2006-02-22, 公開日: 2007-01-16, 最終更新日: 2023-10-25)

主引用文献

Pasquato, N.,Berni, R.,Folli, C.,Alfieri, B.,Cendron, L.,Zanotti, G.
Acidic pH-induced conformational changes in amyloidogenic mutant transthyretin.
J.Mol.Biol., 366:711-719, 2007

PubMed Abstract: Several proteins, including transthyretin (TTR), can generate in tissues extracellular insoluble aggregates, in the form of fibrils, that are associated with pathological states known as amyloidoses. To date, more than 80 different TTR point mutations have been associated with hereditary amyloidosis in humans. In vitro, the formation of amyloid fibrils by human TTR is known to be triggered by acidic pH. We show here that, in vitro, the natural amyloidogenic I84S and the non-natural I84A TTR mutant forms exhibit a propensity to produce fibrils in an acidic medium significantly higher than that of wild-type TTR. The two mutant forms have been crystallized at both neutral and acidic pH. Their neutral pH crystal structures are very similar to that of wild-type TTR, consistent with previous evidence indicating that only minor structural changes are induced by amyloidogenic mutations. On the contrary, their crystal structures at moderately low pH (4.6) show significant conformational differences as compared to their neutral pH structures. Remarkably, such changes are not induced in wild-type TTR crystallized at low pH. The most relevant consist of the unwinding of the TTR short alpha-helix and of the change in conformation of the loop connecting the alpha-helix to beta-strand F. Only one monomer of the crystallographic dimer is affected, causing a disruption of the tetrameric symmetry. This asymmetry and a possible destabilization of the tetrameric quaternary structure of TTR may be responsible for the amyloidogenic potential of the two TTR mutant forms at low pH.

PubMed: 17196219
DOI: 10.1016/j.jmb.2006.11.076

実験手法

X-RAY DIFFRACTION (1.85 Å)