Francisco Serena, Lamacchia Lorenzo, Turco Attilio, Ermondi Giuseppe, Caron Giulia, Rossi Sebastiano Matteo
Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.
Protein Sci. 2025 Jan;34(1):e70006. doi: 10.1002/pro.70006.
This study focuses on spastic paraplegia type 50 (SPG50), an adapter protein complex 4 deficiency syndrome caused by mutations in the adapter protein complex 4 subunit mu-1 (AP4M1) gene, and on the downstream alterations of the AP4M1 protein. We applied a battery of heterogeneous computational resources, encompassing two in-house tools described here for the first time, to (a) assess the druggability potential of AP4M1, (b) characterize SPG50-associated mutations and their 3D scenario, (c) identify mutation-tailored drug candidates for SPG50, and (d) elucidate their mechanisms of action by means of structural considerations on homology models of the adapter protein complex 4 core. Altogether, the collected results indicate R367Q as the mutation with the most promising potential of being corrected by small-molecule drugs, and the flavonoid rutin as best candidate for this purpose. Rutin shows promise in rescuing the interaction between the AP4M1 and adapter protein complex subunit beta-1 (AP4B1) subunits by means of a glue-like mode of action. Overall, this approach offers a framework that could be systematically applied to the investigation of mutation-wise molecular mechanisms in different hereditary spastic paraplegias, too.
本研究聚焦于50型痉挛性截瘫（SPG50），这是一种由衔接蛋白复合体4亚基μ-1（AP4M1）基因突变引起的衔接蛋白复合体4缺乏综合征，以及AP4M1蛋白的下游改变。我们应用了一系列不同的计算资源，包括首次在此描述的两种内部工具，以（a）评估AP4M1的成药潜力，（b）表征与SPG50相关的突变及其三维情况，（c）为SPG50识别针对突变的候选药物，以及（d）通过对衔接蛋白复合体4核心同源模型的结构考量阐明其作用机制。总体而言，收集到的结果表明R367Q是最有希望被小分子药物纠正的突变，而类黄酮芦丁是为此目的的最佳候选药物。芦丁有望通过类似胶水的作用模式挽救AP4M1与衔接蛋白复合体亚基β-1（AP4B1）亚基之间的相互作用。总体而言，这种方法提供了一个框架，该框架也可系统地应用于不同遗传性痉挛性截瘫中逐个突变的分子机制研究。
