Racemic Peptides from Amyloid β and Amylin Form Rippled β-Sheets Rather Than Pleated β-Sheets.
Racemic Peptides from Amyloid β and Amylin Form Rippled β-Sheets Rather Than Pleated β-Sheets.
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来自β淀粉样蛋白和胰淀素的外消旋肽形成波纹状β-片而不是褶状β-片。
DOI：
10.1021/jacs.3c11712
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发表时间：
2023
影响因子：
15
通讯作者：
Raskatov,JevgenijA
中科院分区：
文献类型：
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作者：
Hazari,Amaruka;Sawaya,MichaelR;Sajimon,Maria;Vlahakis,Niko;Rodriguez,Jose;Eisenberg,David;Raskatov,JevgenijA
波林和科里在1953年将波纹β折叠理论化为一种结构基序，其中镜像肽链组装成氢键周期性阵列，具有严格交替的手性。波纹β折叠的结构表征仅限于生物物理方法，直到2022年首次获得基序的原子分辨率结构。晶体结构基础仅限于由芳香残基组成的四种模型三肽。在这里，我们报告了五个新的波纹状片状晶体结构，分别来自淀粉样蛋白β和胰淀素，阿尔茨海默病和II型糖尿病的聚集毒性肽。尽管肽序列组成不同，但所有五种结构都形成反平行的波纹β折叠，这些折叠像原纤维一样沿着结晶针的整个长度延伸。然而，晶体的长程堆积是变化的。在其中三种晶体中，片层面对面地堆积并排除水，从而产生交叉β结构，其与淀粉样蛋白原纤维的空间拉链基序非常相似，但在基本细节上有所不同。在另外两种晶体中，溶剂被封装在薄片之间，产生能够进行主客体化学反应的原纤维结构。我们的研究表明，在三维（3D）组装体中聚集外消旋肽混合物形成波纹β-折叠是一种普遍现象，并为靶向内在无序蛋白质提供了结构基础。
The rippled β-sheet was theorized by Pauling and Corey in 1953 as a structural motif in which mirror image peptide strands assemble into hydrogen-bonded periodic arrays with strictly alternating chirality. Structural characterization of the rippled β-sheet was limited to biophysical methods until 2022 when atomic resolution structures of the motif were first obtained. The crystal structural foundation is restricted to four model tripeptides composed exclusively of aromatic residues. Here, we report five new rippled sheet crystal structures derived from amyloid β and amylin, the aggregating toxic peptides of Alzheimer’s disease and type II diabetes, respectively. Despite the variation in peptide sequence composition, all five structures form antiparallel rippled β-sheets that extend, like a fibril, along the entire length of the crystalline needle. The long-range packing of the crystals, however, varies. In three of the crystals, the sheets pack face-to-face and exclude water, giving rise to cross-β architectures grossly resembling the steric zipper motif of amyloid fibrils but differing in fundamental details. In the other two crystals, the solvent is encapsulated between the sheets, yielding fibril architectures capable of host–guest chemistry. Our study demonstrates that the formation of rippled β-sheets from aggregating racemic peptide mixtures in three-dimensional (3D) assemblies is a general phenomenon and provides a structural basis for targeting intrinsically disordered proteins.