4NIP

GVIGIAQ segment 147-153 from Human Superoxide Dismutase

4NIP の概要

• エントリーDOI: 10.2210/pdb4nip/pdb
• 関連するPDBエントリー: 1NIN 1NIO
• 分子名称: GVTGIAQ segment from Superoxide dismutase [Cu-Zn] (2 entities in total)
• 機能のキーワード: steric zipper, cross-beta spine, amyloid fiber, protein fibril
• 由来する生物種: Homo Sapiens (human)
• 細胞内の位置: Cytoplasm : P00441
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 656.77

構造登録者

Sievers, S.A.,Sawaya, M.R.,Eisenberg, D.,Ivanova, M.I. (登録日: 2013-11-06, 公開日: 2013-12-04, 最終更新日: 2024-02-28)

主引用文献

Ivanova, M.I.,Sievers, S.A.,Guenther, E.L.,Johnson, L.M.,Winkler, D.D.,Galaleldeen, A.,Sawaya, M.R.,Hart, P.J.,Eisenberg, D.S.
Aggregation-triggering segments of SOD1 fibril formation support a common pathway for familial and sporadic ALS.
Proc.Natl.Acad.Sci.USA, 111:197-201, 2014

PubMed Abstract: ALS is a terminal disease of motor neurons that is characterized by accumulation of proteinaceous deposits in affected cells. Pathological deposition of mutated Cu/Zn superoxide dismutase (SOD1) accounts for ∼20% of the familial ALS (fALS) cases. However, understanding the molecular link between mutation and disease has been difficult, given that more than 140 different SOD1 mutants have been observed in fALS patients. In addition, the molecular origin of sporadic ALS (sALS) is unclear. By dissecting the amino acid sequence of SOD1, we identified four short segments with a high propensity for amyloid fibril formation. We find that fALS mutations in these segments do not reduce their propensity to form fibrils. The atomic structures of two fibril-forming segments from the C terminus, (101)DSVISLS(107) and (147)GVIGIAQ(153), reveal tightly packed β-sheets with steric zipper interfaces characteristic of the amyloid state. Based on these structures, we conclude that both C-terminal segments are likely to form aggregates if available for interaction. Proline substitutions in (101)DSVISLS(107) and (147)GVIGIAQ(153) impaired nucleation and fibril growth of full-length protein, confirming that these segments participate in aggregate formation. Our hypothesis is that improper protein maturation and incompletely folded states that render these aggregation-prone segments available for interaction offer a common molecular pathway for sALS and fALS.

PubMed: 24344300
DOI: 10.1073/pnas.1320786110

実験手法

X-RAY DIFFRACTION (1.9 Å)