Institute of Protein Biochemistry, Ulm University, 89081 Ulm, Germany.
Institute of Protein Biochemistry, Ulm University, 89081 Ulm, Germany.
J Mol Biol. 2024 Feb 15;436(4):168441. doi: 10.1016/j.jmb.2024.168441. Epub 2024 Jan 8.
Amyloid resistance is the inability or the reduced susceptibility of an organism to develop amyloidosis. In this study we have analysed the molecular basis of the resistance to systemic AApoAII amyloidosis, which arises from the formation of amyloid fibrils from apolipoprotein A-II (ApoA-II). The disease affects humans and animals, including SAMR1C mice that express the C allele of ApoA-II protein, whereas other mouse strains are resistant to development of amyloidosis due to the expression of other ApoA-II alleles, such as ApoA-IIF. Using cryo-electron microscopy, molecular dynamics simulations and other methods, we have determined the structures of pathogenic AApoAII amyloid fibrils from SAMR1C mice and analysed the structural effects of ApoA-IIF-specific mutational changes. Our data show that these changes render ApoA-IIF incompatible with the specific fibril morphologies, with which ApoA-II protein can become pathogenic in vivo.
淀粉样变性抗性是指生物体无法或降低对淀粉样变性的易感性。在这项研究中，我们分析了全身性 AApoAII 淀粉样变性抗性的分子基础，该抗性源于载脂蛋白 A-II（ApoA-II）形成淀粉样纤维。该疾病影响人类和动物，包括表达载脂蛋白 A-II 蛋白 C 等位基因的 SAMR1C 小鼠，而其他小鼠品系由于表达其他载脂蛋白 A-II 等位基因，如 ApoA-IIF，对淀粉样变性的发展具有抗性。通过使用低温电子显微镜、分子动力学模拟和其他方法，我们确定了来自 SAMR1C 小鼠的致病性 AApoAII 淀粉样纤维的结构，并分析了 ApoA-IIF 特异性突变变化的结构影响。我们的数据表明，这些变化使 ApoA-IIF 与特定的纤维形态不兼容，而载脂蛋白 A-II 蛋白在体内可通过这种形态成为致病性的。
