X‑ray Crystallographic Structures of a Trimer, Dodecamer, and Annular Pore Formed by an Aβ_17–36 β‑Hairpin

High-resolution structures of oligomers formed by the β-amyloid peptide Aβ are needed to understand the molecular basis of Alzheimer’s disease and develop therapies. This paper presents the X-ray crystallographic structures of oligomers formed by a 20-residue peptide segment derived from Aβ. The development of a peptide in which Aβ17–36 is stabilized as a β-hairpin is described, and the X-ray crystallographic structures of oligomers it forms are reported. Two covalent constraints act in tandem to stabilize the Aβ17–36 peptide in a hairpin conformation: a δ-linked ornithine turn connecting positions 17 and 36 to create a macrocycle and an intramolecular disulfide linkage between positions 24 and 29. An N-methyl group at position 33 blocks uncontrolled aggregation. The peptide readily crystallizes as a folded β-hairpin, which assembles hierarchically in the crystal lattice. Three β-hairpin monomers assemble to form a triangular trimer, four trimers assemble in a tetrahedral arrangement to form a dodecamer, and five dodecamers pack together to form an annular pore. This hierarchical assembly provides a model, in which full-length Aβ transitions from an unfolded monomer to a folded β-hairpin, which assembles to form oligomers that further pack to form an annular pore. This model may provide a better understanding of the molecular basis of Alzheimer’s disease at atomic resolution.解析β淀粉样肽（β-amyloid peptide, Aβ）所形成寡聚体的高分辨率结构，是理解阿尔茨海默病（Alzheimer’s disease）分子机制并开发治疗策略的必要前提。本研究报道了源自Aβ的20残基肽段所形成寡聚体的X射线晶体学（X-ray crystallographic）结构。文中详述了一种可将Aβ₁₇–₃₆稳定为β发夹结构（β-hairpin）的肽段设计方案，并报告了该肽段所形成寡聚体的X射线晶体学结构。两种共价约束协同作用，将Aβ₁₇–₃₆肽段稳定为发夹构象：一是连接第17与36位残基以形成大环（macrocycle）的δ连接鸟氨酸转角（δ-linked ornithine turn），二是位于第24与29位残基之间的分子内二硫键（intramolecular disulfide linkage）。第33位残基处的N-甲基（N-methyl）可阻断无控聚集。该肽段易于结晶为折叠态β发夹结构，并在晶格（crystal lattice）中按层级方式组装：三个β发夹单体组装形成三角形三聚体（trimer），四个三聚体以四面体排布（tetrahedral arrangement）构成十二聚体（dodecamer），五个十二聚体进一步堆叠形成环形孔道（annular pore）。这种层级组装机制构建了一个模型，即全长Aβ从解折叠单体转变为折叠的β发夹结构，进而组装为寡聚体，最终堆叠形成环形孔道。该模型有望在原子分辨率（atomic resolution）层面加深我们对阿尔茨海默病分子机制的理解。