4E0N

SVQIVYK segment from human Tau (305-311) displayed on 54-membered macrocycle scaffold (form II)

4E0N の概要

• エントリーDOI: 10.2210/pdb4e0n/pdb
• 関連するPDBエントリー: 4E0K 4E0L 4E0M 4E0O
• 分子名称: Cyclic pseudo-peptide SVQIVYK(ORN)EF(HAO)(4BF)K(ORN), PHOSPHATE ION, (4S)-2-METHYL-2,4-PENTANEDIOL, ... (4 entities in total)
• 機能のキーワード: amyloid, out-of-register, fiber-forming, macrocycle, protein fibril
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 8817.00

構造登録者

Zhao, M.,Liu, C.,Michael, S.R.,Eisenberg, D. (登録日: 2012-03-04, 公開日: 2012-12-19, 最終更新日: 2023-11-15)

主引用文献

Liu, C.,Zhao, M.,Jiang, L.,Cheng, P.N.,Park, J.,Sawaya, M.R.,Pensalfini, A.,Gou, D.,Berk, A.J.,Glabe, C.G.,Nowick, J.,Eisenberg, D.
Out-of-register beta-sheets suggest a pathway to toxic amyloid aggregates.
Proc.Natl.Acad.Sci.USA, 109:20913-20918, 2012

PubMed Abstract: Although aberrant protein aggregation has been conclusively linked to dozens of devastating amyloid diseases, scientists remain puzzled about the molecular features that render amyloid fibrils or small oligomers toxic. Here, we report a previously unobserved type of amyloid fibril that tests as cytotoxic: one in which the strands of the contributing β-sheets are out of register. In all amyloid fibrils previously characterized at the molecular level, only in-register β-sheets have been observed, in which each strand makes its full complement of hydrogen bonds with the strands above and below it in the fibril. In out-of-register sheets, strands are sheared relative to one another, leaving dangling hydrogen bonds. Based on this finding, we designed out-of-register β-sheet amyloid mimics, which form both cylindrin-like oligomers and fibrils, and these mimics are cytotoxic. Structural and energetic considerations suggest that out-of-register fibrils can readily convert to toxic cylindrins. We propose that out-of-register β-sheets and their related cylindrins are part of a toxic amyloid pathway, which is distinct from the more energetically favored in-register amyloid pathway.

PubMed: 23213214
DOI: 10.1073/pnas.1218792109

実験手法

X-RAY DIFFRACTION (1.65 Å)