Institute of Protein Biochemistry, Ulm University, 89081, Ulm, Germany.
Medical Department V, Section of Multiple Myeloma, Heidelberg University Hospital, 69120, Heidelberg, Germany.
Nat Commun. 2019 Mar 20;10(1):1103. doi: 10.1038/s41467-019-09032-0.
Amyloid fibrils derived from antibody light chains are key pathogenic agents in systemic AL amyloidosis. They can be deposited in multiple organs but cardiac amyloid is the major risk factor of mortality. Here we report the structure of a λ1 AL amyloid fibril from an explanted human heart at a resolution of 3.3 Å which we determined using cryo-electron microscopy. The fibril core consists of a 91-residue segment presenting an all-beta fold with ten mutagenic changes compared to the germ line. The conformation differs substantially from natively folded light chains: a rotational switch around the intramolecular disulphide bond being the crucial structural rearrangement underlying fibril formation. Our structure provides insight into the mechanism of protein misfolding and the role of patient-specific mutations in pathogenicity.
抗体轻链衍生的淀粉样纤维是系统性 AL 淀粉样变性的关键致病因子。它们可以沉积在多个器官中，但心脏淀粉样变是主要的死亡风险因素。在这里，我们报道了一个从植入的人类心脏中提取的λ1 AL 淀粉样纤维的结构，分辨率为 3.3Å，我们使用冷冻电子显微镜来确定其结构。纤维核心由一个 91 个残基的片段组成，呈现出全β折叠结构，与原始轻链相比有 10 个突变。该构象与天然折叠的轻链有很大不同：分子内二硫键的旋转开关是纤维形成的关键结构重排。我们的结构为蛋白质错误折叠的机制以及患者特异性突变在致病性中的作用提供了深入的了解。
