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Papillomavirus E6 Structural Consortium

乳头瘤病毒 E6 结构联盟

基本信息

批准号：
9280613
负责人：
Scott Brian Vande Pol
金额：
$ 44.35万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-02-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9280613
关键词：
Animals Benign Epithelioma Binding Binding Proteins Biological Biological Process Biology Bovine Papillomavirus Bovine Papillomavirus-1 Cancer Etiology Cervix Uteri Complex Crystallization Dimensions Distant Docking First Independent Research Support and Transition Awards Funding Genital system HIV Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Human Human Papillomavirus Human papillomavirus 16 Immunocompromised Host Intervention Knowledge Life Cycle Stages Low risk HPV Maintenance Malignant Neoplasms Malignant epithelioma Malignant neoplasm of anus Medical Modeling Molecular Molecular Conformation Molecular Structure Mutagenesis Mutation Neck Cancer Oncoproteins Papillomaviridae Papillomavirus Peptides Persons Phenotype Phosphorylation Plasmids Production Protein p53 Proteins Risk Role Shapes Signal Transduction Structural Protein Structure Surface TP53 gene Testing Transcription Coactivator UBE3A gene Vertebrates Viral Viral Genome Virus cell immortalization cellular targeting clinically significant design high risk immortalized cell immunosuppressed in vivo insight notch protein paxillin protein protein interaction public health relevance respiratory skin squamous cell carcinoma

项目摘要

DESCRIPTION (provided by applicant): Papillomaviruses cause benign and malignant epitheliomas in vertebrates, and are grouped into genera of related viruses. Alpha genus HPV's cause anogenital and head and neck cancers that arise from the influence of the virally encoded E6 and E7 oncoproteins. Beta genus HPV types are associated with cutaneous squamous cell carcinomas in immunosuppressed patients, and other HPV types can cause disabling warts in immunosuppressed and HIV infected persons. The action of the virally encoded E6 oncoprotein is critical for the production of both benign epitheliomas and cancers in all HPV types, and the cancer phenotype can be inhibited if E6 expression is inhibited. Therefore, an understanding of the structure of E6 and how E6 interacts with its cellular targets is critical to potential interventions. In the first award cycle of this renewal application, we defined the three dimensional molecular structure of E6 proteins bound to their cellular targets, which is a finding that had been sought for decades. In addition, this application elucidated a newly described cellular target of beta genus E6 called MAML1. MAML1 is a transcriptional coactivator of Notch signaling, so discovery of this association is an important advance in understanding the biology of both human (MAML is the target of E6 proteins in the beta and mu genera) and animal E6 proteins. When E6 proteins bind their cellular targets (called LxxLL docking motifs in the target protein), they undergo an allosteric change in shape to interact with additional proteins such as the p53 tumor suppressor. In this renewal application, we will extend the analysis of E6 structure to additional E6 proteins of medical importance, determine at the molecular level how E6 interacts with additional cellular proteins such as the p53 tumor suppressor, and determine the surface domains of E6 that are required for critical aspects of the papillomavirus life cycle.

描述（由申请方提供）：乳头瘤病毒在脊椎动物中引起良性和恶性上皮瘤，并分为相关病毒属。α属HPV引起肛门生殖器和头颈部癌症，这些癌症是由病毒编码的E6和E7癌蛋白的影响引起的。β属HPV类型与免疫抑制患者的皮肤鳞状细胞癌相关，其他HPV类型可导致免疫抑制和HIV感染者的致残性疣。病毒编码的E6癌蛋白的作用对于所有HPV类型中良性上皮瘤和癌症的产生都是至关重要的，并且如果E6表达被抑制，则癌症表型可以被抑制。因此，了解E6的结构以及E6如何与其细胞靶点相互作用对潜在的干预至关重要。在此次更新申请的第一个奖项周期中，我们定义了与其细胞靶点结合的E6蛋白的三维分子结构，这是几十年来一直在寻找的发现。此外，本申请阐明了一种新描述的β属E6的细胞靶标，称为MAML1。MAML 1是Notch信号传导的转录共激活因子，因此这种关联的发现是理解人类（MAML是β和μ属中E6蛋白的靶标）和动物E6蛋白生物学的重要进展。当E6蛋白结合其细胞靶点（在靶蛋白中称为LxxLL对接基序）时，它们经历形状的变构变化以与其他蛋白质如p53肿瘤抑制因子相互作用。在此更新申请中，我们将扩展E6结构的分析，以额外的E6蛋白的医学重要性，确定在分子水平上如何E6与其他细胞蛋白，如p53肿瘤抑制因子相互作用，并确定所需的乳头瘤病毒生命周期的关键方面的E6的表面结构域。