Gamete Membrane Adhesion and Fusion During Fertilization

受精过程中配子膜的粘附和融合

• 批准号: 9197304
• 负责人: William J Snell
• 金额: $ 26.6万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9197304
• 关键词: Adhesions; Algae; Alpha Cell; Binding; Binding Proteins; Biochemical; Biochemistry; Bioinformatics; Biological; Biological Assay; Biological Models; Cell Adhesion Molecules; Cell membrane; Cells; Chimeric Proteins; Chlamydomonas; Chlamydomonas reinhardtii; Cnidaria; Complex; Contraceptive Agents; Contraceptive methods; Coupled; Cysteine; Cytoplasmic Tail; Development; Event; Family member; Female; Fertility; Fertilization; Flagella; Genes; Genetic; Germ Cells; Green Algae; Human; Huntingtin-Associated protein 1; Infertility; Insecta; Knowledge; Laboratories; Life; Lipid Bilayers; Mating Types; Membrane; Membrane Fusion; Methods; Modeling; Modification; Molecular; Nuclear Family; Organism; PDAP2 Gene; Partner in relationship; Pathogenicity; Phase; Physiological; Plasmodium; Porifera; Process; Property; Proteins; Reaction; Reproductive Biology; Research; Role; Set protein; Site; Sperm-Ovum Interactions; Sterility; Structure; Surface; System; Testing; Time; Vascular Plant; Viral Fusion Proteins; Virus; Work; cell motility; env Gene Products; infertility treatment; malaria transmission-blocking vaccine; male; membrane reconstitution; mutant; novel strategies; pathogen; protein function; public health relevance; receptor; receptor binding; sex; transcriptome; transmission process; treatment strategy; vaccine development; zygote

 DESCRIPTION (provided by applicant): Fertilization is an ancient process whose essence is an interaction between two single cells that culminates in creation of one cell. A cell of one sex - typically driven by a flagellum - - contacts a cell of the opposite sex, one or both are activate, and then they fuse. We still lack fundamental information about the molecules and mechanisms that accomplish metazoan gamete fusion and a candidate vertebrate gamete fusion protein remains unidentified. The unicellular, biflagellated alga Chlamydomonas is a unique entry point into studying and understanding the evolutionary development of fertilization. In Chlamydomonas, recognition and adhesion between the highly motile plus and minus gametes bring them together and trigger both to erect cell membrane sites specialized for fusion, the mating structures. Attachment and bilayer merger of the two membranes are genetically distinguishable. Pre-fusion attachment requires interaction of FUS1 on the plus mating structure with MAR1 on the minus mating structure. Bilayer merger depends on the broadly conserved HAP2 protein on the minus mating structure. These requirements for two sets of proteins and for HAP2 in fusion have been confirmed in protists and higher plants and are implicated in some metazoans. Plasmodium HAP2 has become a target for a transmission-blocking malaria vaccine. New studies of functional domains of HAP2 have identified a motif in the cytoplasmic domain essential for targeting to the site of fusion and a conserved cytoplasmic motif that regulates the fusion function of the protein. A new comprehensive analysis of the Chlamydomonas transcriptome has identified a set of genes that are uniquely expressed in gametes and revealed a previously unrecognized family of nuclear envelope proteins essential for zygotic pronuclear fusion across domains of life. Biochemical studies show that MAR1 and HAP2 interact with each within the membrane of the mating structure membrane of minus gametes, and that FUS1, MAR1, and HAP2 are in a common complex during the membrane fusion reaction. More information is available about the cellular and molecular underpinning of gamete fusion in Chlamydomonas than in any other organism. Understanding, for at least one organism, the molecular events that occur during the gamete membrane fusion reaction will establish a framework for dissecting fundamental principles of gamete fusion in other organisms and will lead to development of vaccines to block fertilization of human parasitic pathogens, to development of contraceptives, and to treatments for infertility. The objective of the research proposed here is to test the model that HAP2 functions as a fusion protein during the membrane fusion reaction. The aims are to identify domains of HAP2 required for fusion and investigate whether the HAP2-MAR1 interaction is essential for the fusion function of HAP2; to examine the unique properties of the specialized FUS1-MAR1-dependent adhesion junction that contribute to bilayer fusion; and to identify the minimal set of proteins required to reconstitute the membrane fusion reaction in a heterologous system.

 描述（由适用提供）：受精是一个古老的过程，其本质是两个单个细胞之间的相互作用，最终导致创建一个细胞。一个性别的细胞 - 通常由鞭毛驱动 - - 接触异性的细胞，一个或两个都被激活，然后融合。我们仍然缺乏有关完成后代配子融合的分子和机制和候选脊椎动物配子融合蛋白的基本信息。单精，双足化的藻类衣原体是研究和了解受精的进化发展的独特入口。在衣原体中，高度动感和减去游戏之间的识别和粘合剂将它们聚集在一起，并触发两者都建立了专门用于融合（交配结构）的细胞膜位点。这两个膜的附着和双层合并在遗传上是可以区分的。融合前的附着需要FUS1在加上交配结构与MAR1上的交配结构上的相互作用。双层合并取决于宽的hap2蛋白在减去交配结构上。这些对两组蛋白质和融合中HAP2的要求已在原生和较高的植物中得到证实，并在某些后代人实施。疟原虫HAP2已成为传播阻滞疟疾疫苗的靶标。 HAP2功能结构域的新研究已经确定了靶向融合位点所必需的细胞质结构域和调节蛋白质融合功能的组成的细胞质基序所必需的。对衣原体转录组的新综合分析已经确定了一组在游戏中以唯一表达的基因，并揭示了先前未识别的核包膜蛋白家族，这对于跨生活领域的二细蛋白融合必不可少。生化研究表明，MAR1和HAP2与减去游戏的交配结构膜的膜内相互作用，而FUS1，MAR1和HAP2在膜融合反应中处于共同的复合体中。关于衣原体中配子融合的细胞和分子基础的更多信息比在任何其他生物体中。了解至少一个生物，在配子膜融合反应期间发生的分子事件将建立一个框架，以剖析其他生物体中配子融合的基本原理，并将导致疫苗的发展以阻止人类寄生虫病原体的受精，避孕剂的发展以及对地下的治疗。此处提出的研究的目的是测试HAP2在膜融合反应过程中用作融合蛋白的模型。目的是确定融合所需的HAP2域，并研究HAP2-MAR1相互作用是否对于HAP2的融合函数至关重要。检查有助于双层融合的专用FUS1-MAR1依赖性粘附连接的独特性能；并确定重建异源系统中膜融合反应所需的最小蛋白质集。

项目成果

Targeting the Conserved Fusion Loop of HAP2 Inhibits the Transmission of Plasmodium berghei and falciparum.

• DOI: 10.1016/j.celrep.2017.11.024
• 发表时间: 2017-12-05
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Angrisano F;Sala KA;Da DF;Liu Y;Pei J;Grishin NV;Snell WJ;Blagborough AM
• 通讯作者: Blagborough AM

Plant sperm need a little help.

植物精子需要一点帮助。

• DOI: 10.1038/s41477-019-0385-0
• 发表时间: 2019
• 期刊: Nature plants
• 影响因子: 18
• 作者: Zhang,Jun;Pinello,JenniferF;Snell,WilliamJ
• 通讯作者: Snell,WilliamJ

MAR1 links membrane adhesion to membrane merger during cell-cell fusion in Chlamydomonas.

• DOI: 10.1016/j.devcel.2021.10.023
• 发表时间: 2021-12-20
• 期刊: Developmental cell
• 影响因子: 11.8
• 作者: Pinello JF;Liu Y;Snell WJ
• 通讯作者: Snell WJ

Development. Plant gametes do fertilization with a twist.

发展。

• DOI: 10.1126/science.1231259
• 发表时间: 2012
• 期刊: Science (New York, N.Y.)
• 作者: Snell,WilliamJ

The Ancient Gamete Fusogen HAP2 Is a Eukaryotic Class II Fusion Protein.

• DOI: 10.1016/j.cell.2017.01.024
• 发表时间: 2017-02-23
• 期刊: Cell
• 影响因子: 64.5
• 作者: Fédry J;Liu Y;Péhau-Arnaudet G;Pei J;Li W;Tortorici MA;Traincard F;Meola A;Bricogne G;Grishin NV;Snell WJ;Rey FA;Krey T
• 通讯作者: Krey T