5TXH

Polymorphic form 2 of amyloid-beta derived peptide - IFAEDV

5TXH の概要

• エントリーDOI: 10.2210/pdb5txh/pdb
• 関連するPDBエントリー: 5TXD 5TXJ
• 分子名称: IFAEDV, ISOPROPYL ALCOHOL (3 entities in total)
• 機能のキーワード: protein fibril, de novo protein
• 由来する生物種: Homo sapiens
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 2831.12

構造登録者

Sangwan, S.,Sawaya, M.R.,Eisenberg, D. (登録日: 2016-11-16, 公開日: 2017-11-15, 最終更新日: 2024-04-03)

主引用文献

Do, T.D.,Sangwan, S.,de Almeida, N.E.C.,Ilitchev, A.I.,Giammona, M.,Sawaya, M.R.,Buratto, S.K.,Eisenberg, D.S.,Bowers, M.T.
Distal amyloid beta-protein fragments template amyloid assembly.
Protein Sci., 27:1181-1190, 2018

PubMed Abstract: Amyloid formation is associated with devastating diseases such as Alzheimer's, Parkinson's and Type-2 diabetes. The large amyloid deposits found in patients suffering from these diseases have remained difficult to probe by structural means. Recent NMR models also predict heterotypic interactions from distinct peptide fragments but limited evidence of heterotypic packed sheets is observed in solution. Here we characterize two segments of the protein amyloid β (Aβ) known to form fibrils in Alzheimer's disease patients. We designed two variants of Aβ(19-24) and Aβ(27-32), IFAEDV (I6V) and NKGAIF (N6F) to lower the aggregation propensity of individual peptides while maintaining the similar interactions between the two segments in their native forms. We found that the variants do not form significant amyloid fibrils individually but a 1:1 mixture forms abundant fibrils. Using ion mobility-mass spectrometry (IM-MS), hetero-oligomers up to decamers were found in the mixture while the individual peptides formed primarily dimers and some tetramers consistent with a strong heterotypic interaction between the two segments. We showed by X-ray crystallography that I6V formed a Class 7 zipper with a weakly packed pair of β-sheets and no segregated dry interface, while N6F formed a more stable Class 1 zipper. In a mixture of equimolar N6F:I6V, I6V forms a more stable zipper than in I6V alone while no N6F or hetero-typic zippers are observed. These data are consistent with a mechanism where N6F catalyzes assembly of I6V into a stable zipper and perhaps into stable, pure I6V fibrils that are observed in AFM measurements.

PubMed: 29349888
DOI: 10.1002/pro.3375

実験手法

X-RAY DIFFRACTION (1.45 Å)