Mondal Sunil Kanti, Sen Madhab Kumar
Department of Biotechnology, The University of Burdwan, Burdwan, 713104, West Bengal, India.
Department of Agricultural Biotechnology, Ramakrishna Mission Vivekananda Education & Research Institution, Narendrapur, Kolkata, 700103, West Bengal, India.
Heliyon. 2020 Jan 6;6(1):e03106. doi: 10.1016/j.heliyon.2019.e03106. eCollection 2020 Jan.
The tumour suppressor gene, PTEN (Phosphatase and Tensin homolog deleted on chromosome Ten), can act as both protein phosphatase and lipid phosphatase, is known to play a vital role in Pi3k signalling pathway. In humans, it is located at 10q23. Loss of its phosphatase and catalytic activity is associated with various types of cancers. This study focuses on evolution, understanding the somatic missense mutation in a particular residue of PTEN and understanding the molecular mechanism that leads to endometrial carcinoma through molecular docking. Mutational analysis of H123 position indicates that the missense mutation at first position of the codon CAC by G or T, result in aspartic acid or tyrosine instead of histidine and can have negative effect on the function of PTEN. Alongside, structural analysis showed mutated PTEN has lower stability than the normal. Additionally, SNPs dataset for endometrial carcinoma suggests H123 as strongly mutated residue. The mutation in phosphatase domain of PTEN along with its effect and interaction with substrate TLA1352 were systematically studied through molecular docking. Molecular interaction study reveals that the optimal substrate binding site in PTEN is unable to interact with the substrate in the mutated condition. This observation drew attention on the impact of mutation on disease biology and enabled us to conduct follow-up studies to retrieve novel molecular targets, such as mutated protein domain and modified Asp and Tyr sites, to design effective therapies to either prevent endometrial carcinoma or impede its progression.
肿瘤抑制基因PTEN（第10号染色体缺失的磷酸酶及张力蛋白同源物）可作为蛋白磷酸酶和脂质磷酸酶发挥作用，已知其在Pi3k信号通路中起着至关重要的作用。在人类中，它位于10q23。其磷酸酶和催化活性的丧失与多种类型的癌症相关。本研究聚焦于进化，了解PTEN特定残基中的体细胞错义突变，并通过分子对接了解导致子宫内膜癌的分子机制。H123位置的突变分析表明，密码子CAC的第一位由G或T发生错义突变，会导致天冬氨酸或酪氨酸取代组氨酸，可能对PTEN的功能产生负面影响。同时，结构分析显示突变后的PTEN稳定性低于正常PTEN。此外，子宫内膜癌的单核苷酸多态性数据集表明H123是高度突变的残基。通过分子对接系统地研究了PTEN磷酸酶结构域中的突变及其对底物TLA1352的影响和相互作用。分子相互作用研究表明，PTEN中最佳的底物结合位点在突变状态下无法与底物相互作用。这一观察结果引起了人们对突变对疾病生物学影响的关注，并使我们能够开展后续研究以寻找新的分子靶点，如突变的蛋白结构域以及修饰的天冬氨酸和酪氨酸位点，从而设计有效的疗法来预防子宫内膜癌或阻止其进展。
