Molecular Basis of mRNA Export
mRNA 输出的分子基础
基本信息
- 批准号:9007944
- 负责人:
- 金额:$ 34.21万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-02-05 至 2020-01-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteArchitectureBindingBinding SitesBiochemicalBiological AssayBloodBrain DiseasesCell NucleusCell physiologyCellsCharacteristicsChildCodeComplexComplicationConsensusCytoplasmCytoplasmic FilamentsCytoplasmic ProteinDNADataDevelopmentDiseaseDockingElementsEncephalopathiesEndoplasmic ReticulumEtiologyEukaryotaEventEvolutionExhibitsFaceFoundationsFunctional disorderFutureGene Expression RegulationGenesGeneticGenetic TranscriptionGenetic TranslationGoalsHomologous GeneHumanImmune systemIn VitroInflammatoryInheritedLeadMediatingMembraneMethodsModificationMolecularMutationN-terminalNuclear EnvelopeNuclear ExportNuclear Pore ComplexNuclear Pore Complex ProteinsNucleotidesPathway interactionsPatientsPeptide Signal SequencesPlayPredispositionProductionProtein BiosynthesisProteinsProteomeRNARampRecruitment ActivityRegulationReporterResearchRoleShapesSideSiteSolidStructureSusceptibility GeneTherapeuticTranscriptTranslationsVariantVertebratesViralVirulence FactorsVirusVirus DiseasesYeastsbasebrain tissuecytokinedesignelectron tomographygenetic informationhuman diseasein vivoinsightmRNA Exportmacromoleculemolecular massneoplasticnovel therapeuticsnucleocytoplasmic transportpolypeptidepreventprotein expressionprotein protein interactionpublic health relevancereconstructionsecretory proteinsegregationtargeted treatment
项目摘要
DESCRIPTION (provided by applicant): One of the great hallmarks of evolution is the enclosure of genetic information in the nucleus. The spatial segregation of replication and transcription in the nucleus and translation in the cytoplasm imposes the requirement of transporting thousands of macromolecules between these two compartments. Nuclear pore complexes (NPCs) are the sole gateways that allow bi-directional macromolecular exchange across the nuclear envelope and thus function as key regulators of the flow of genetic information from DNA to RNA to protein. The NPC is a massive transport channel that is constructed by ~30 distinct proteins, termed nucleoporins (nups), which assemble into six evolutionarily conserved subcomplexes. Due to 8-fold symmetry, each subcomplex is present in multiple copies in the fully assembled NPC, such that the entire assembly reaches the extraordinary molecular mass of ~120 MDa in vertebrates. The NPC coat, a protein shell that directly interacts with the inner and outer membranes of the nuclear envelope, is assembled from multiple copies of the hetero-heptameric coat nucleoporin complex (CNC). The NPC coat anchors the donut-shaped NPC core harboring the central transport channel, and provides key binding sites for asymmetric nucleoporins on its exposed nucleoplasmic and cytoplasmic faces that, in turn, recruit various transcription and mRNA export machineries to the NPC. These associated machineries establish transport directionality and allow the NPC to play a major role in gene regulation. As such, it is unsurprising that genetic modifications of asymmetric nucleoporins have been associated with a diverse set of human conditions, such as neoplastic diseases or susceptibility to escalating viral infections. In higher eukaryotes, the asymmetric cytoplasmic filament nucleoporin Nup358, which has no homolog in single-cell eukaryotes, is required for the efficient synthesis of secretory proteins that depends on an alternative RNA export (ALREX) pathway. ALREX mRNAs are characterized by a signal sequence-coding region (SSCR), which encodes the short hydrophobic consensus polypeptide required for protein targeting to the endoplasmic reticulum. At the cytoplasmic face of the NPC, Nup358 interacts with ALREX mRNAs through direct binding to their SSCR and is required for their efficient translation. In human Nup358, the domain mediating SSCR binding has been identified as a susceptibility locus for a hereditary form of acute necrotizing encephalopathy (ANE), a rare but severe condition developed by some children upon common viral infections. Although the etiology of ANE remains unknown, increased levels of pro-inflammatory cytokines in combination with the shared involvement of Nup358 in the ALREX pathway as well as ANE support the hypothesis that a deregulation of secretory protein expression may play a relevant role. In this proposal, we seek to elucidate the atomic architecture of the cytoplasmic face of the
NPC and establish the molecular mechanism of ALREX pathway regulation by Nup358 while assessing its relevance to secretory protein synthesis and ANE. These goals will be achieved through a combination of biochemical, structural and functional approaches designed to dissect molecular interactions between the relevant nucleoporins including wild type and ANE-associated Nup358 variants and SSCR RNA. Overall, our research will contribute to the understanding of fundamental mRNA export mechanisms with particular relevance to the synthesis of the secretory proteome and may provide therapeutically important clues to human diseases associated with mRNA export dysfunction and the development of ANE, a frequently untreatable and ultimately fatal nucleoporin disease.
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Andre Hoelz其他文献
Andre Hoelz的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Andre Hoelz', 18)}}的其他基金
Supplement: Atomic Structure of the Nuclear Pore Complex
补充:核孔复合体的原子结构
- 批准号:
10705495 - 财政年份:2014
- 资助金额:
$ 34.21万 - 项目类别:
Supplement: Atomic Structure of the Nuclear Pore Complex
补充:核孔复合体的原子结构
- 批准号:
10390118 - 财政年份:2014
- 资助金额:
$ 34.21万 - 项目类别:
相似海外基金
CAREER: Efficient Algorithms for Modern Computer Architecture
职业:现代计算机架构的高效算法
- 批准号:
2339310 - 财政年份:2024
- 资助金额:
$ 34.21万 - 项目类别:
Continuing Grant
Hardware-aware Network Architecture Search under ML Training workloads
ML 训练工作负载下的硬件感知网络架构搜索
- 批准号:
2904511 - 财政年份:2024
- 资助金额:
$ 34.21万 - 项目类别:
Studentship
CAREER: Creating Tough, Sustainable Materials Using Fracture Size-Effects and Architecture
职业:利用断裂尺寸效应和架构创造坚韧、可持续的材料
- 批准号:
2339197 - 财政年份:2024
- 资助金额:
$ 34.21万 - 项目类别:
Standard Grant
Travel: Student Travel Support for the 51st International Symposium on Computer Architecture (ISCA)
旅行:第 51 届计算机体系结构国际研讨会 (ISCA) 的学生旅行支持
- 批准号:
2409279 - 财政年份:2024
- 资助金额:
$ 34.21万 - 项目类别:
Standard Grant
Understanding Architecture Hierarchy of Polymer Networks to Control Mechanical Responses
了解聚合物网络的架构层次结构以控制机械响应
- 批准号:
2419386 - 财政年份:2024
- 资助金额:
$ 34.21万 - 项目类别:
Standard Grant
I-Corps: Highly Scalable Differential Power Processing Architecture
I-Corps:高度可扩展的差分电源处理架构
- 批准号:
2348571 - 财政年份:2024
- 资助金额:
$ 34.21万 - 项目类别:
Standard Grant
Collaborative Research: Merging Human Creativity with Computational Intelligence for the Design of Next Generation Responsive Architecture
协作研究:将人类创造力与计算智能相结合,设计下一代响应式架构
- 批准号:
2329759 - 财政年份:2024
- 资助金额:
$ 34.21万 - 项目类别:
Standard Grant
The architecture and evolution of host control in a microbial symbiosis
微生物共生中宿主控制的结构和进化
- 批准号:
BB/X014657/1 - 财政年份:2024
- 资助金额:
$ 34.21万 - 项目类别:
Research Grant
RACCTURK: Rock-cut Architecture and Christian Communities in Turkey, from Antiquity to 1923
RACCTURK:土耳其的岩石建筑和基督教社区,从古代到 1923 年
- 批准号:
EP/Y028120/1 - 财政年份:2024
- 资助金额:
$ 34.21万 - 项目类别:
Fellowship
NSF Convergence Accelerator Track M: Bio-Inspired Surface Design for High Performance Mechanical Tracking Solar Collection Skins in Architecture
NSF Convergence Accelerator Track M:建筑中高性能机械跟踪太阳能收集表皮的仿生表面设计
- 批准号:
2344424 - 财政年份:2024
- 资助金额:
$ 34.21万 - 项目类别:
Standard Grant