Structural mutation analysis of PTEN and its possible genotype-phenotype correlat

PTEN的结构突变分析及其可能的基因型-表型相关性

• 批准号: 8459049
• 负责人: Iris Nira Smith
• 金额: $ 2.77万
• 依托单位: UNIVERSITY OF HOUSTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-12 至 2017-09-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8459049
• 关键词: Active Sites; Affect; Age; Binding; Bioinformatics; C2 Domain; Cancer Cluster; Catalysis; Cell Proliferation; Cell Survival; Charge; Chromosomes; Chromosomes, Human, Pair 10; Classification; Clinical; Data; Development; Diagnosis; Disease; Electrostatics; Endometrial Carcinoma; Endometrial Hyperplasia; Endometrium; Etiology; Event; Genes; Genotype; Human; Hydrogen Bonding; Incidence; Investigation; Ligands; Literature; Location; Malignant Neoplasms; Malignant neoplasm of ovary; Maps; Membrane; Methods; Modification; Molecular; Molecular Conformation; Molecular Models; Mutate; Oncogenic; PTEN gene; Pathogenesis; Pathway interactions; Patients; Phenotype; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Phosphoric Monoester Hydrolases; Phosphotransferases; Play; Publishing; Reporting; Research; Role; Signal Pathway; Structure; Symptoms; Techniques; Therapeutic; Tissues; Translations; Tumor Suppressor Proteins; Woman; endometriosis; flexibility; loss of function; molecular dynamics; molecular modeling; novel diagnostics; novel therapeutic intervention; novel therapeutics; phosphatidylinositol 3,4,5-triphosphate; social; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Structural mutation analysis of PTEN and its possible genotype-phenotype correlations in Endometriosis and Cancer The phosphatase and tensin homolog deleted on chromosome ten (PTEN) gene encodes a tumor suppressor phosphatase frequently mutated in a variety of human cancers. It exerts its function by dephosphorylating phosphatidylinositol 3,4,5-triphosphate (PIP3), converting it to phosphatidylinositol 4,5-bisphosphate (PIP2). PIP3 activates a variety of downstream effectors that turn on the PI3K/Akt oncogenic pathway leading to unregulated cell proliferation and tumorigenesis. Loss of function and somatic missense mutations of PTEN have recently been found in patients with endometriosis, endometrial cancer and ovarian cancer although no structural information on these mutations is currently available. Through the cross-referencing of published literature, the phenotypes of distinct PTEN mutations affecting the signature motif of the catalytic phosphatase domain and C2 domain were identified. Among these mutations, moderate phenotypes were associated with endometriosis and endometrial hyperplasia and are distributed throughout both domains. Whereas the more severe phenotypes were associated with endometrial cancer and ovarian cancer and are clustered in the signature motif (H123CXXGXXR130) that forms the P loop at the bottom of the active site pocket. The signature motif contains residues that play a crucial role in loop conformation (H123 and G127) and are essential for catalysis (C124 and R130). One distinct residue within the active site R130, has mutations implicated in both moderate and severe phenotypes. In this proposed study, we will explore the structural effects that the identified PTEN mutations have on the relationship between genotype and phenotype, and investigate the specific molecular mechanisms involved. Molecular dynamics simulations wil be used to examine the clustered mutations to characterize their effects on P loop conformations and the functional distortions they may impose within the active site as well as mutations within the C2 domain that may affect PTEN's ability to interact with the membrane. We propose mutations within the active site disrupt the electrostatic interaction thus affecting P loop conformation. Loop flexibility imposed by these missense mutations may affect the binding of PTEN to its ligand and adversely affect the PI3K/Akt signaling pathway. Understanding the functional impact that these missense mutations have on the structure of PTEN is essential to elucidating the molecular mechanism of endometriosis, endometrial cancer and ovarian cancer in the development of novel therapeutics. PUBLIC HEALTH RELEVANCE: Endometriosis is a common, highly enigmatic gynecological disease affecting an estimated 176 million women worldwide showing no disparity towards age, ethnic, or social circumstances. Currently there is no known cure, however treatment options are available to manage symptoms associated with the disease. This proposal is aimed at gaining, at the molecular level, an understanding of and mapping the structural alterations (mutations) in PTEN associated with endometriosis and cancer to aid in the development of commercially viable therapeutics in the treatment and ultimately the cure of endometriosis. !

描述（由申请人提供）：子宫内膜异位症和癌症中PTEN的结构突变分析及其可能的基因型-表型相关性第十号染色体上缺失的磷酸酶和紧张素同源物（PTEN）基因编码一种在多种人类癌症中经常发生突变的肿瘤抑制磷酸酶。它通过去磷酸化磷脂酰肌醇3,4,5-三磷酸（PIP3），将其转化为磷脂酰肌醇4,5-二磷酸（PIP2）来发挥其功能。PIP3激活多种下游效应物，这些效应物开启PI3K/Akt致癌途径，导致不受调节的细胞增殖和肿瘤发生。最近在子宫内膜异位症、子宫内膜癌和卵巢癌患者中发现了PTEN的功能丧失和体细胞错义突变，尽管目前还没有关于这些突变的结构信息。通过交叉引用已发表的文献，鉴定了影响催化磷酸酶结构域和C2结构域特征基序的不同PTEN突变的表型。在这些突变中，中等表型与子宫内膜异位症和子宫内膜增生有关，并且分布在这两个领域。而更严重的表型则与子宫内膜癌和卵巢癌相关，并聚集在活性位点口袋底部形成P环的特征基序（H123CXXGXXR130）中。该特征基序包含在环构象（H123和G127）和催化（C124和R130）中起关键作用的残基。在活性位点R130中有一个明显的残基，在中度和重度表型中都有突变。在本研究中，我们将探讨已鉴定的PTEN突变对基因型和表型关系的结构影响，并探讨其具体的分子机制。分子动力学模拟将用于检查簇状突变，以表征它们对P环构象的影响，以及它们可能在活性位点内施加的功能扭曲，以及可能影响PTEN与膜相互作用能力的C2结构域突变。我们提出活性位点内的突变破坏静电相互作用从而影响P环构象。这些错义突变所施加的环灵活性可能影响PTEN与其配体的结合，并对PI3K/Akt信号通路产生不利影响。了解这些错义突变对PTEN结构的功能影响，对于阐明子宫内膜异位症、子宫内膜癌和卵巢癌的分子机制以及开发新的治疗方法至关重要。