School of Biological Sciences, Nanyang Technological University, Singapore, 637551, Singapore.
Department of Biology, Shenzhen MSU-BIT University, 518172, Shenzhen, China.
Commun Biol. 2023 Mar 30;6(1):348. doi: 10.1038/s42003-023-04725-1.
TGFBI-related corneal dystrophy (CD) is characterized by the accumulation of insoluble protein deposits in the corneal tissues, eventually leading to progressive corneal opacity. Here we show that ATP-independent amyloid-β chaperone L-PGDS can effectively disaggregate corneal amyloids in surgically excised human cornea of TGFBI-CD patients and release trapped amyloid hallmark proteins. Since the mechanism of amyloid disassembly by ATP-independent chaperones is unknown, we reconstructed atomic models of the amyloids self-assembled from TGFBIp-derived peptides and their complex with L-PGDS using cryo-EM and NMR. We show that L-PGDS specifically recognizes structurally frustrated regions in the amyloids and releases those frustrations. The released free energy increases the chaperone's binding affinity to amyloids, resulting in local restructuring and breakage of amyloids to protofibrils. Our mechanistic model provides insights into the alternative source of energy utilized by ATP-independent disaggregases and highlights the possibility of using these chaperones as treatment strategies for different types of amyloid-related diseases.
TGFBI 相关角膜营养不良 (CD) 的特征是角膜组织中不可溶蛋白沉积物的积累，最终导致进行性角膜混浊。在这里，我们表明，ATP 非依赖性淀粉样蛋白β伴侣 L-PGDS 可以有效解聚 TGFBI-CD 患者手术切除的人眼角膜中的角膜淀粉样蛋白，并释放被困的淀粉样蛋白标志性蛋白。由于 ATP 非依赖性伴侣解聚淀粉样蛋白的机制尚不清楚，我们使用 cryo-EM 和 NMR 重建了源自 TGFBIp 衍生肽的淀粉样蛋白自组装及其与 L-PGDS 复合物的原子模型。我们表明，L-PGDS 特异性识别淀粉样蛋白中的结构受挫区域，并释放这些受挫区域。释放的自由能增加了伴侣与淀粉样蛋白的结合亲和力，导致局部重排和淀粉样蛋白断裂为原纤维。我们的机制模型提供了对 ATP 非依赖性解聚酶利用的替代能量来源的深入了解，并强调了使用这些伴侣作为不同类型淀粉样蛋白相关疾病治疗策略的可能性。
