Viral oncoproteins: Revealing novel structural motifs to target tumor suppressors
病毒癌蛋白:揭示靶向肿瘤抑制因子的新结构基序
基本信息
- 批准号:8849868
- 负责人:
- 金额:$ 40.26万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-06-01 至 2019-04-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAdenovirusesAffinityAvidityBindingBinding SitesBiological AssayBiologyC-terminalCell NucleusCleaved cellComplexDNA Tumor VirusesDevelopmentDimerizationDominant-Negative MutationEngineeringEpigenetic ProcessEvolutionGene TargetingGenesGenomic approachGenomicsGoalsHealthHeterochromatinHigher Order Chromatin StructureHomologous GeneInfectionKnowledgeMalignant NeoplasmsModelingMolecularMutagenesisMutateMutationNBS1 geneNuclearOncogene ProteinsOncogenesOncolyticPathway interactionsPeptidesPolymersProteinsResearchRoleSiteStructureSubgroupTailTestingTherapeutic AgentsTumor Suppressor ProteinsViralViral CancerViral GenesViral GenomeViral ProteinsVirusVirus Diseasesbasecancer therapycell growthcellular targetingcomparative genomicsdimerinsightlytic replicationmutantneoplastic cellnext generationnovelnovel therapeuticsprotein protein interactionstructural biologytherapeutic targettumor
项目摘要
DESCRIPTION (provided by applicant): This proposal will reveal the structural mechanisms and motifs that enable a tiny viral oncoprotein to target and disrupt multiple critical tumor suppressor pathways. The ultimate goal is to exploit this knowledge to develop novel viral therapies against intractable tumor targets. The evolution of minimal DNA tumor virus' genomes has selected for small viral oncoproteins that hijack critical cellular protein interaction network that are also targeted by mutations in cancer. However, the structural basis for the dominant interactions of small adenovirus oncoproteins has remained elusive, as none of their complete structures have been solved. This represents a fundamental gap in the understanding of Adenovirus biology and the structural principles that enable small viral proteins to 'win'. To address this the structure of an E4-ORF3 dimer at 2.1¿ was solved. E4-ORF3 is a 13kDa protein that assembles a nuclear polymer network that binds and disrupts the PML, TRIM24, and MRE11/RAD50/NBS1 (MRN) tumor suppressor complexes. In addition, E4-ORF3 induces heterochromatin silencing at p53 target genes and anti-viral genes through an unknown mechanism. In contrast to the archetypal Adenovirus oncoprotein, E1A, E4-ORF3 has a discrete ordered structure and is not a structural homologue of any known cellular polymers or oncogenes. E4-ORF3 forms dimer subunits with a central beta-core that further co-assemble through reciprocal and non-reciprocal exchanges of their C-terminal tails. The higher order assembly of E4-ORF3 is required for creating avidity-driven interactions with PML and an emergent MRN binding interface. This proposed research builds on these studies. Aim 1 will reveal the structure and higher order oligomeric interactions that drive the assembly of wild type E4-ORF3 and are required for its functions in disrupting multiple tumor suppressors to facilitate viral replication. Aim 2 will use the structure of E4-ORF3 as a rational basis to identify new structural motifs that target the PML, MRN and TRIM24 tumor suppressor complexes, which are important therapeutic targets. Discrete E4-ORF3 mutations will be engineered that selectively uncouple its interactions with different tumor suppressor complexes to reveal their respective contributions in viral infection. This will provide a rational basis for the development of novel vral cancer therapies that selectively replicate in tumor cells with particular tumor suppressor pathway mutations. E4-ORF3 dimerization creates a novel binding-cleft that determines the sites of its assembly in the nucleus and is required for silencing p53 target genes. Aim 3 will use
a combination of viral engineering and integrative comparative genomics approaches to determine if residues within the cleft target the E4-ORF3 assembly to specific genomic loci where it binds to a motif in H10 and to induce repressive heterochromatin silencing of p53 and anti-viral genes. This will reveal new targets and mechanisms that silence p53 in infection and that could also be disrupted by mutations in cancer.
描述(由适用提供):该建议将揭示结构机制和基序,这些机制和基序使小病毒癌蛋白能够靶向和破坏多个关键肿瘤抑制途径。最终目标是利用这种知识来开发针对棘手的肿瘤靶标的新型病毒疗法。最小DNA肿瘤病毒的基因组的进化已选择用于小型病毒癌蛋白,劫持了临界细胞蛋白相互作用网络,这些网络也受到癌症突变的靶向。但是,小腺病毒癌蛋白主要相互作用的结构基础仍然难以捉摸,因为它们的完整结构均未解决。这代表了理解腺病毒生物学的基本差距以及使小病毒蛋白获得“胜利”的结构原理。为了解决这一问题,在2.1¿E4-ORF3处的E4-ORF3二聚体的结构是一种13KDA蛋白,该蛋白组装了核聚合物网络,该网络结合并破坏PML,TRIM24和MRE11/RAD50/NBS1(MRN)肿瘤抑制剂抑制剂复合物。此外,E4-ORF3通过未知机制在p53靶基因和抗病毒基因处诱导异染色质沉默。与原型腺病毒癌蛋白E1A,E4-ORF3具有离散的有序结构相反,并且不是任何已知的细胞聚合物或癌基因的结构同源物。 E4-ORF3与中央β-核形成二聚体亚基,该亚基通过其C末端尾巴的倒数和非重新交换,进一步共同组装。 E4-ORF3的高阶组件是与PML和新兴的MRN结合界面建立自行驱动的相互作用所必需的。这项研究基于这些研究。 AIM 1将揭示驱动野生型E4-ORF3组装的结构和高阶寡聚相互作用,并且其在破坏多种肿瘤补充剂以促进病毒复制方面的功能是必需的。 AIM 2将使用E4-ORF3的结构作为合理的基础,以确定针对PML,MRN和TRIM24肿瘤抑制剂复合物的新结构基序,这是重要的治疗靶标。将设计离散的E4-ORF3突变,以选择性地使其与不同肿瘤抑制剂复合物相互作用,以揭示其在病毒感染中的各自贡献。这将为开发新型的vral癌疗法的发展提供合理的基础,这些疗法在具有特定肿瘤抑制途径突变的肿瘤细胞中有选择地复制。 E4-ORF3二聚化创建了一种新型的结合键,该结合键确定其在核中的组装位点,并且是沉积p53靶基因所必需的。 AIM 3将使用
病毒工程和综合基因组学方法的结合,以确定在裂口内消退的E4-ORF3组件在特定的基因组基因座中与H10中的基序结合并影响反射性异色素对P53和抗病毒基因的沉默。这将揭示新的靶标和机制,这些靶标和机制使p53沉默,并且也可能因癌症突变而破坏。
项目成果
期刊论文数量(0)
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会议论文数量(0)
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Clodagh O'Shea其他文献
Clodagh O'Shea的其他文献
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{{ truncateString('Clodagh O'Shea', 18)}}的其他基金
Viral oncoproteins: Revealing novel structural motifs to target tumor suppressors
病毒癌蛋白:揭示靶向肿瘤抑制因子的新结构基序
- 批准号:
8696462 - 财政年份:2014
- 资助金额:
$ 40.26万 - 项目类别:
A NOVEL NUCLEAR STRUCTURE THAT SILENCES P53 ACTIVITY
一种抑制 P53 活性的新型核结构
- 批准号:
8361942 - 财政年份:2011
- 资助金额:
$ 40.26万 - 项目类别:
Defining critical p53 therapeutic targets and mechanisms
定义关键的 p53 治疗靶点和机制
- 批准号:
8013884 - 财政年份:2009
- 资助金额:
$ 40.26万 - 项目类别:
Defining Critical p53 Therapeutic Targets and Mechanisms
定义关键的 p53 治疗靶点和机制
- 批准号:
8818821 - 财政年份:2009
- 资助金额:
$ 40.26万 - 项目类别:
Defining critical p53 therapeutic targets and mechanisms
定义关键的 p53 治疗靶点和机制
- 批准号:
7567632 - 财政年份:2009
- 资助金额:
$ 40.26万 - 项目类别:
Defining critical p53 therapeutic targets and mechanisms
定义关键的 p53 治疗靶点和机制
- 批准号:
8212429 - 财政年份:2009
- 资助金额:
$ 40.26万 - 项目类别:
Defining Critical p53 Therapeutic Targets and Mechanisms
定义关键的 p53 治疗靶点和机制
- 批准号:
8986160 - 财政年份:2009
- 资助金额:
$ 40.26万 - 项目类别:
Defining critical p53 therapeutic targets and mechanisms
定义关键的 p53 治疗靶点和机制
- 批准号:
8433990 - 财政年份:2009
- 资助金额:
$ 40.26万 - 项目类别:
Defining Critical p53 Therapeutic Targets and Mechanisms
定义关键的 p53 治疗靶点和机制
- 批准号:
9180687 - 财政年份:2009
- 资助金额:
$ 40.26万 - 项目类别:
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