Laboratory for Biomolecular Structure and Function, Department of Biotechnology, University of Rijeka, 51000 Rijeka, Croatia.
Laboratory for Medical Biochemistry, Psychiatric Hospital Rab, Kampor 224, 51280 Rab, Croatia.
Int J Mol Sci. 2023 Jan 17;24(3):1835. doi: 10.3390/ijms24031835.
Pathogenic changes in γ-secretase activity, along with its response to different drugs, can be affected by changes in the saturation of γ-secretase with its substrate. We analyze the saturation of γ-secretase with its substrate using multiscale molecular dynamics studies. We found that an increase in the saturation of γ-secretase with its substrate could result in the parallel binding of different substrate molecules at the docking site and the active site. The C-terminal domain of the substrate bound at the docking site can interact with the most dynamic presenilin sites at the cytosolic end of the active site tunnel. Such interactions can inhibit the ongoing catalytic activity and increase the production of the longer, more hydrophobic, and more toxic Aβ proteins. Similar disruptions in dynamic presenilin structures can be observed with different drugs and disease-causing mutations. Both, C99-βCTF-APP substrate and its different Aβ products, can support the toxic aggregation. The aggregation depends on the substrate N-terminal domain. Thus, the C99-βCTF-APP substrate and β-secretase path can be more toxic than the C83-αCTF-APP substrate and α-secretase path. Nicastrin can control the toxic aggregation in the closed conformation. The binding of the C99-βCTF-APP substrate to γ-secretase can be controlled by substrate channeling between the nicastrin and β-secretase. We conclude that the presented two-substrate mechanism could explain the pathogenic changes in γ-secretase activity and Aβ metabolism in different sporadic and familial cases of Alzheimer's disease. Future drug-development efforts should target different cellular mechanisms that regulate the optimal balance between γ-secretase activity and amyloid metabolism.
γ-分泌酶活性的致病变化及其对不同药物的反应，可能受到 γ-分泌酶与其底物饱和度变化的影响。我们通过多尺度分子动力学研究分析了 γ-分泌酶与其底物的饱和度。我们发现，γ-分泌酶与其底物的饱和度增加可能导致不同底物分子在对接位点和活性位点的平行结合。结合在对接位点的底物的 C 端结构域可以与活性位点隧道胞质末端最动态的早老素结合位点相互作用。这种相互作用可以抑制正在进行的催化活性，并增加更长、疏水性更强、毒性更大的 Aβ 蛋白的产生。不同的药物和致病突变也会观察到类似的早老素结构动态破坏。C99-βCTF-APP 底物及其不同的 Aβ 产物都可以支持毒性聚集。聚集取决于底物的 N 端结构域。因此，C99-βCTF-APP 底物和β-分泌酶途径可能比 C83-αCTF-APP 底物和α-分泌酶途径更具毒性。尼卡斯特林可以控制封闭构象中的毒性聚集。C99-βCTF-APP 底物与 γ-分泌酶的结合可以通过尼卡斯特林和β-分泌酶之间的底物通道化来控制。我们得出结论，所提出的双底物机制可以解释不同散发性和家族性阿尔茨海默病病例中 γ-分泌酶活性和 Aβ 代谢的致病变化。未来的药物开发工作应针对不同的细胞机制，以调节 γ-分泌酶活性和淀粉样蛋白代谢之间的最佳平衡。
