Papillomavirus E6 Structural Consortium

 描述(申请人提供)：乳头瘤病毒导致脊椎动物的良性和恶性上皮瘤，并被归类为相关病毒的属。甲型HPV会导致肛门癌和头颈癌，这些癌症是由病毒编码的E6和E7癌蛋白的影响引起的。在免疫抑制的患者中，β属HPV类型与皮肤鳞状细胞癌有关，而其他类型的HPV可能会在免疫抑制和艾滋病毒感染者中导致致残疣。病毒编码的E6癌蛋白的作用对于所有HPV类型的良性上皮瘤和癌的产生都是关键的，如果E6的表达被抑制，癌症的表型可以被抑制。因此，了解E6的结构以及E6如何与其细胞靶点相互作用对于潜在的干预至关重要。在此次续展申请的第一个获奖周期中，我们定义了与其细胞靶标结合的E6蛋白的三维分子结构，这是人们几十年来一直在寻找的发现。此外，这一应用阐明了一个新描述的β属E6的细胞靶点，称为MAML1。MAML1是Notch信号的转录共激活因子，因此这种关联的发现对于理解人类(MAML是β和Mu属E6蛋白的靶标)和动物E6蛋白的生物学都是一个重要的进步。当E6蛋白与它们的细胞靶标结合时(在靶蛋白中称为LxxLL对接基序)，它们经历变构的形状变化，与其他蛋白质如p53肿瘤抑制因子相互作用。在这一更新应用中，我们将把对E6结构的分析扩展到更多具有医学意义的E6蛋白，在分子水平上确定E6如何与其他细胞蛋白(如p53肿瘤抑制因子)相互作用，并确定E6的表面域，这些是乳头瘤病毒生命周期的关键方面所必需的。

 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.