Laquatra Claudio, Magro Alessia, Guarra Federica, Lambrughi Matteo, Ferrone Lavinia, Fracasso Giulio, Bacchin Melissa, La Spina Martina, Moroni Elisabetta, Papaleo Elena, Colombo Giorgio, Rasola Andrea
Department of Biomedical Sciences, University of Padova, Padova, Italy.
Department of Chemistry, University of Pavia, Pavia, Italy.
Cell Death Dis. 2025 Mar 12;16(1):172. doi: 10.1038/s41419-025-07467-6.
The mitochondrial chaperone TRAP1 is a key regulator of cellular homeostasis and its activity has important implications in neurodegeneration, ischemia and cancer. Recent evidence has indicated that TRAP1 mutations are involved in several disorders, even though the structural basis for the impact of point mutations on TRAP1 functions has never been studied. By exploiting a modular structure-based framework and molecular dynamics simulations, we investigated the effect of five TRAP1 mutations on its structure and stability. Each mutation differentially impacts long-range interactions, intra and inter-protomer dynamics and ATPase activity. Changes in these parameters influence TRAP1 functions, as revealed by their effects on the activity of the TRAP1 interactor succinate dehydrogenase (SDH). In keeping with this, TRAP1 point mutations affect the growth and migration of aggressive sarcoma cells, and alter sensitivity to a selective TRAP1 inhibitor. Our work provides new insights on the structure-activity relationship of TRAP1, identifying crucial amino acid residues that regulate TRAP1 proteostatic functions and pro-neoplastic activity.
线粒体伴侣蛋白TRAP1是细胞稳态的关键调节因子，其活性在神经退行性变、局部缺血和癌症中具有重要意义。最近的证据表明，TRAP1突变与多种疾病有关，尽管点突变对TRAP1功能影响的结构基础从未被研究过。通过利用基于模块化结构的框架和分子动力学模拟，我们研究了五个TRAP1突变对其结构和稳定性的影响。每个突变对远程相互作用、亚基内和亚基间动力学以及ATP酶活性有不同的影响。这些参数的变化影响TRAP1的功能，这通过它们对TRAP1相互作用蛋白琥珀酸脱氢酶（SDH）活性的影响得以揭示。与此一致的是，TRAP1点突变影响侵袭性肉瘤细胞的生长和迁移，并改变对选择性TRAP1抑制剂的敏感性。我们的工作为TRAP1的构效关系提供了新的见解，确定了调节TRAP1蛋白质稳态功能和促肿瘤活性的关键氨基酸残基。
