Cellular and molecular mechanisms regulating function of a broadly conserved gamete membrane fusogen
广泛保守的配子膜融合剂功能的细胞和分子机制调节
基本信息
- 批准号:10228351
- 负责人:
- 金额:$ 1.97万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-09 至 2020-12-23
- 项目状态:已结题
- 来源:
- 关键词:AdhesionsAnimal ModelAntibodiesBackBindingBiochemicalBiological ModelsCRISPR/Cas technologyCell membraneCellsChimeric ProteinsChlamydomonasChordataCulicidaeCysteineDengueDevelopmentDissociationEndosomesEnsureEukaryotaEventEvolutionGel ChromatographyGenesGerm CellsGreen AlgaeHumanHuntingtin-Associated protein 1HydrophobicityImpairmentIn VitroLaboratoriesLeadLengthMalariaMating TypesMembraneMembrane FusionMembrane ProteinsMethodsModelingMolecularMolecular ConformationMutationOrganismPDAP2 GenePartner in relationshipPeptidesPlasmodiumPlasmodium falciparumProteinsPublishingReactionRecombinantsReproductionResearchRoleSignal PathwaySignal TransductionStructureSystemTestingTimeTransmembrane DomainVascular PlantViralViral Fusion ProteinsVirusZIKAbasecell motilitydimerexperimental studyfield studyfungushuman pathogenimprovedin vivoinsightmolecular massmonomermutantpathogensedimentation velocitytransmission processtrimer corevirus envelopezygote
项目摘要
Project Summary
Our understanding of the molecular mechanisms of fusion between reproductive cells (gametes)
during sexual reproduction is surprisingly limited. In studies with the unicellular green alga,
Chlamydomonas and the malaria pathogen Plasmodium, the Snell laboratory has shown that the
broadly conserved, gamete-specific membrane protein HAP2 (also called GCS1) is essential for
bilayer merger during gamete fusion. HAP2 acts after tight adhesion of gamete plasma
membranes, and is present on only one of the two gametes (e.g., mating type minus gametes in
Chlamydomonas) and therefore functions unilaterally, as do viral fusion proteins during their entry
into host cells. Remarkably, recent collaborative structure/function studies demonstrated that
Chlamydomonas HAP2 is structurally homologous to the class II fusion proteins of many
enveloped viruses, including dengue and Zika. Though recombinant forms of the ectodomain of
Chlamydomonas HAP2 form trimers in vitro and the hydrophobic fusion loop is essential for
function in vivo, we still know very little about the molecular mechanism of this eukaryotic class
II fusion protein during gamete fusion in any HAP2 organism. Endogenous trimers that
presumably form during gamete fusion have yet to be detected, and the mechanisms are
unknown that restrict triggering of trimer formation until the HAP2-bearing gamete undergoes
specific membrane interaction with the membrane of its partner gamete. In preliminary
experiments, I have discovered a stable oligomer, which appears only after gamete fusion, and is
likely to be the endogenous HAP2 trimer. I have also determined that, unlike with the viral class
II proteins, low pH fails to trigger oligomer formation of HAP2. Rather, the HAP2-containing
minus mating structure must bind to the adhesion protein FUS1 on the plus mating structure,
ensuring that triggering takes place only at the right time and place. This research aims to define
the molecular mechanisms that underlie the function of a broadly conserved eukaryotic
membrane fusogen that is essential for fusion of gametes in organisms across kingdoms. The
insights gained from this study will improve our understanding of fundamental, conserved
mechanisms of gamete fusion, and have the potential to yield improved strategies for interfering
with sexual reproduction and transmission of organism that harm humans, including the
devastating malaria organism Plasmodium. Here, I will test the model that a new HAP2 oligomer
detected in gametes after fusion is a trimer. I will investigate structural features of HAP2 required
for oligomerization. And, I will investigate the mechanisms that underlie FUS1-dependent
triggering of HAP2 structural rearrangements.
项目摘要
我们对生殖细胞(配子)融合的分子机制的理解
在有性繁殖过程中是令人惊讶的有限的。在对单细胞绿藻的研究中,
衣藻和疟疾病原体疟原虫,斯内尔实验室已经表明
广泛保守的配子特异性膜蛋白HAP2(也称为GCS1)是
配子融合过程中的双层合并。HAP2在配子血浆紧密粘连后起作用
膜,只存在于两个配子中的一个配子上(例如,交配型减去配子
衣藻),因此起单边作用,正如病毒融合蛋白在进入体内时一样
进入宿主细胞。值得注意的是,最近的协作结构/功能研究表明
衣藻HAP2在结构上与许多
包膜病毒,包括登革热和寨卡病毒。通过重组形式的胞外结构域
衣藻HAP2在体外形成三聚体,疏水融合环是
在体内发挥作用,但我们对这类真核生物的分子机制仍然知之甚少。
II任何HAP2生物体配子融合过程中的融合蛋白。内源性三聚体
可能是在配子融合过程中形成的,目前还没有发现,其机制是
在携带HAP2的配子完成之前,限制三聚体形成的未知因素
特异膜与配子配子的膜相互作用。在预赛中
实验中,我发现了一种稳定的低聚物,它只有在配子融合后才出现,并且是
可能是内源性HAP2三聚体。我还确定,与病毒课不同的是
II蛋白,低pH不能引发HAP2寡聚体的形成。相反,含有HAP2的
负交配结构必须与正交配结构上的黏附蛋白FUS1结合,
确保触发只在正确的时间和地点发生。这项研究旨在定义
广泛保守的真核生物功能的分子机制
跨王国生物体中配子融合所必需的膜FusoGen。这个
从这项研究中获得的见解将提高我们对基本的、保守的
配子融合的机制,并有可能产生改进的干扰策略
有性繁殖和危害人类的有机体的传播,包括
毁灭性的疟疾生物疟原虫。在这里,我将测试一种新的HAP2齐聚物的模型
融合后的配子中检测到一种三聚体。我将调查所需的HAP2的结构特征
用于寡聚反应。并且,我将研究依赖于FUS1的机制
触发HAP2结构重排。
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)
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Jun Zhang其他文献
Jun Zhang的其他文献
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{{ truncateString('Jun Zhang', 18)}}的其他基金
The central roles of SRSF1 in early-stage spliceosome assembly
SRSF1 在早期剪接体组装中的核心作用
- 批准号:
10797788 - 财政年份:2022
- 资助金额:
$ 1.97万 - 项目类别:
The central roles of SRSF1 in early-stage spliceosome assembly
SRSF1 在早期剪接体组装中的核心作用
- 批准号:
10678784 - 财政年份:2022
- 资助金额:
$ 1.97万 - 项目类别:
The central roles of SRSF1 in early-stage spliceosome assembly
SRSF1 在早期剪接体组装中的核心作用
- 批准号:
10501047 - 财政年份:2022
- 资助金额:
$ 1.97万 - 项目类别:
Cellular and molecular mechanisms regulating function of a broadly conserved gamete membrane fusogen
广泛保守的配子膜融合剂功能的细胞和分子机制调节
- 批准号:
9761105 - 财政年份:2019
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Evaluation of obstructive sleep apnea with long range 3D endoscopic FDOCT
使用远距离 3D 内窥镜 FDOCT 评估阻塞性睡眠呼吸暂停
- 批准号:
8274654 - 财政年份:2011
- 资助金额:
$ 1.97万 - 项目类别:
Evaluation of obstructive sleep apnea with long range 3D endoscopic FDOCT
使用远距离 3D 内窥镜 FDOCT 评估阻塞性睡眠呼吸暂停
- 批准号:
8499397 - 财政年份:2011
- 资助金额:
$ 1.97万 - 项目类别:
Evaluation of obstructive sleep apnea with long range 3D endoscopic FDOCT
使用远距离 3D 内窥镜 FDOCT 评估阻塞性睡眠呼吸暂停
- 批准号:
8656561 - 财政年份:2011
- 资助金额:
$ 1.97万 - 项目类别:
Evaluation of obstructive sleep apnea with long range 3D endoscopic FDOCT
使用远距离 3D 内窥镜 FDOCT 评估阻塞性睡眠呼吸暂停
- 批准号:
8046502 - 财政年份:2011
- 资助金额:
$ 1.97万 - 项目类别:
Molecular and cellular etiology of cerebral cavernous malformations
脑海绵状血管瘤的分子和细胞病因学
- 批准号:
7990816 - 财政年份:2010
- 资助金额:
$ 1.97万 - 项目类别:
Molecular and cellular etiology of cerebral cavernous malformations
脑海绵状血管瘤的分子和细胞病因学
- 批准号:
8067037 - 财政年份:2010
- 资助金额:
$ 1.97万 - 项目类别:
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