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: 8709825
• 负责人: Iris Nira Smith
• 金额: $ 2.82万
• 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/8709825
• 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.

描述（由申请人提供）：PTEN的结构突变分析及其在子宫内膜异位症和癌症中可能的基因型 - 表型相关性，在染色体第十（PTEN）上磷酸酶和Tensin同源性删除编码肿瘤抑制剂磷酸酶经常在各种人类癌中突变。它通过脱磷酸化磷脂酰肌醇3,4,5-三磷酸（PIP3）来发挥其功能，将其转化为磷脂酰肌醇4,5-双磷酸盐（PIP2）。 PIP3激活了各种下游效应子，这些效应子打开PI3K/AKT致癌途径，导致不受管制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功能丧失和PTEN的体义突变，尽管目前尚无有关这些突变的结构信息。通过对已发表文献的交叉引用，确定了影响催化磷酸酶结构域和C2结构域的特征基序的不同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，并分布在两个域中。而更严重的表型与子宫内膜癌和卵巢癌有关，并聚集在签名基序（H123CXXGXXR130）中，该基序形成了活跃部位口袋底部的P环。签名基序包含残基在环构象中起着至关重要的作用（H123和G127），对于催化至关重要（C124和R130）。活性位点R130中的一个不同的残基，其突变与中度和重度表型有关。在这项拟议的研究中，我们将探讨已鉴定的PTEN突变对基因型和表型之间关系的结构效应，并研究所涉及的特定分子机制。分子动力学模拟将用于检查聚类突变，以表征其对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C2结构域内可能影响PTEN与膜与膜相互作用的突变。我们建议在活动位点内的突变破坏静电相互作用，从而影响P循环构象。这些错义突变施加的环灵活性可能会影响PTEN与其配体的结合，并不利地影响PI3K/AKT信号通路。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至关重要。