Goutam Rajen K, Huang Gangtong, Medina Exequiel, Ding Feng, Edenfield William J, Sanabria Hugo
Department of Physics and Astronomy, Clemson University, Clemson, 29634, SC, USA.
Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Chile.
Res Sq. 2024 Dec 19:rs.3.rs-5225582. doi: 10.21203/rs.3.rs-5225582/v1.
The ARID1A gene, frequently mutated in cancer, encodes the AT-rich interactive domain-containing protein 1A, a key component of the chromatin remodeling SWI/SNF complex. The ARID1A protein features a conserved DNA-binding domain (ARID domain) of approximately 100 residues crucial for its function. Despite the frequency of mutations, the impact on ARID1A's stability and contribution to cancer progression remains unclear. We analyzed five frequent missense mutations R1020S, M1022K, K1047Q, G1063V, and A1089T identified in The Cancer Genome Atlas (TCGA) to assess their effects on the stability of the ARID domain using a hybrid experimental and computational approach. By combining computational stability from web server tools, the structural dynamics from replica exchange discrete molecular simulation (rexDMD), and thermal and chemical denaturation experiments, we found that the R1020S mutation severely decreases structural stability, making it the most impactful, while M1022K has minimal effect, and others lie in between. These findings enhance our understanding of the structural-functional relationship of ARID1A missense mutations at the molecular levels and their role in cancer pathogenesis. This research paves the way for identifying and categorizing which ARID1A mutations are most pathogenic, potentially guiding the development of targeted therapies tailored to specific mutation profiles in cancer treatment.
ARID1A基因在癌症中经常发生突变，它编码富含AT的相互作用结构域蛋白1A，这是染色质重塑SWI/SNF复合体的关键组成部分。ARID1A蛋白具有一个由约100个残基组成的保守DNA结合结构域（ARID结构域），该结构域对其功能至关重要。尽管突变频繁，但ARID1A稳定性的影响及其对癌症进展的作用仍不清楚。我们分析了在癌症基因组图谱（TCGA）中鉴定出的五个常见错义突变R1020S、M1022K、K1047Q、G1063V和A1089T，使用混合实验和计算方法评估它们对ARID结构域稳定性的影响。通过结合网络服务器工具的计算稳定性、副本交换离散分子模拟（rexDMD）的结构动力学以及热变性和化学变性实验，我们发现R1020S突变严重降低了结构稳定性，使其影响最大，而M1022K的影响最小，其他突变则介于两者之间。这些发现增强了我们在分子水平上对ARID1A错义突变的结构-功能关系及其在癌症发病机制中作用的理解。这项研究为识别和分类哪些ARID1A突变最具致病性铺平了道路，有可能指导针对癌症治疗中特定突变谱的靶向治疗的开发。
