Hicks Chad W, Prokaeva Tatiana, Spencer Brian, Jayaraman Shobini, Huda Noorul, Wong Sherry, Chen Hui, Sanchorawala Vaishali, Lavatelli Francesca, Gursky Olga
Department of Pharmacology, Physiology & Biophysics, Chobanian & Avedisian School of Medicine, Boston University, Boston, MA, USA.
Amyloidosis Center, Chobanian & Avedisian School of Medicine, Boston University, Boston, MA, USA.
bioRxiv. 2025 Jul 1:2025.06.25.661559. doi: 10.1101/2025.06.25.661559.
In amyloid light chain (AL) amyloidosis, aberrant monoclonal antibody light chains (LCs) deposit in vital organs causing organ damage. Each AL patient features a unique LC. Previous cryogenic electron microscopy (cryo-EM) studies revealed different amyloid structures in different AL patients. How LC mutations influence amyloid structures remains unclear. We report a cryo-EM structure of cardiac AL-224L amyloid (2.92 Å resolution) from λ6-LC family, which is overrepresented in amyloidosis. Comparison with λ6-LC structures from two other patients reveals similarities in amyloid folds. Mutation-induced structural differences in AL-224L include altered C-terminal conformation with an exposed ligand-binding surface; an enlarged hydrophilic pore with orphan density; and altered steric zipper registry with backbone flipping, which likely represent general adaptive mechanisms in amyloids. The results suggest shared features in λ6-LC amyloid folds and reveal how mutation-induced structural changes influence amyloid-ligand interactions in a patient-specific manner.
在淀粉样轻链（AL）淀粉样变性中，异常的单克隆抗体轻链（LCs）沉积在重要器官中，导致器官损伤。每个AL患者都有独特的LC。先前的低温电子显微镜（cryo-EM）研究揭示了不同AL患者中不同的淀粉样结构。LC突变如何影响淀粉样结构仍不清楚。我们报道了来自λ6-LC家族的心脏AL-224L淀粉样蛋白的低温电子显微镜结构（分辨率为2.92 Å），该家族在淀粉样变性中占比过高。与另外两名患者的λ6-LC结构进行比较，发现淀粉样折叠存在相似性。AL-224L中突变引起的结构差异包括：C端构象改变，配体结合表面暴露；亲水性孔扩大，有孤立密度；空间拉链排列改变，主链翻转，这可能代表淀粉样蛋白中的一般适应性机制。结果表明λ6-LC淀粉样折叠具有共同特征，并揭示了突变引起的结构变化如何以患者特异性方式影响淀粉样蛋白与配体的相互作用。
