Structural mechanisms and evolution of egg-sperm interactions

卵子-精子相互作用的结构机制和进化

• 批准号: 9137515
• 负责人: Damien Beau Wilburn
• 金额: $ 5.61万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9137515
• 关键词: Acrosome; Address; Affinity; Animal Model; Animals; Binding; Biochemical; Biological; Biological Assay; Capsid Proteins; Complement; Complex; Conflict (Psychology); Development; Docking; Egg Proteins; Evolution; Female; Fertilization; Genes; Genetic Materials; Genetic Models; Glycoproteins; Homology Modeling; Human; Hydrogen Bonding; In Vitro; Incidence; Infertility; Invertebrates; Investigation; Knowledge; Marines; Measures; Mediating; Membrane Fusion; Methods; Modeling; Molecular; Mutation; Nucleotides; Oocytes; Organism; Pattern; Point Mutation; Protein Dynamics; Proteins; Proteomics; Quantitative Genetics; Recording of previous events; Reproductive Biology; Reproductive Health; Research; Resolution; Roentgen Rays; Scanning; Site; Sperm-Ovum Interactions; Structure; Study models; System; Techniques; Testing; Theoretical model; Vertebrates; X-Ray Crystallography; Zona Pellucida; abalone; base; design; egg; infertility treatment; innovation; insight; lysin; male; novel; novel strategies; novel therapeutics; preference; protein function; public health relevance; receptor; reproductive; research study; response; sample fixation; screening; sperm cell; sperm protein; three dimensional structure; trait

 DESCRIPTION (provided by applicant): The incidence of infertility has increased 4% since the 1980s, with up to 20% cases having no known cause. One of the prevailing hypotheses is incompatibility between cognate egg and sperm proteins; however, very few pairs of interacting reproductive proteins have been identified in any organism. The best model for studying fertilization remains the marine gastropod abalone, where one of the first steps in fertilization involves the interaction between the sperm protein lysin and its egg coat receptor VERL. As a major component of the abalone egg coat, VERL is a giant, fibrous glycoprotein composed of ~22 ZP-N repeats that form intermolecular hydrogen bonds to create the highly stabilized and protective egg coat. Lysin creates a hole in the egg coat by competing for the hydrogen bonds, allowing sperm to pass and fuse with the oocyte. The VERL repeats are homologous to human egg coat proteins, and likely share a similar protein topology. However, the precise structural mechanisms that drive egg coat dissolution remains to be determined. To address this fundamental question in fertilization, two specific aims are proposed using state-of-the-art structural and proteomic approaches. In aim 1, multidimensional NMR will be used to characterize the structural basis of lysin-VERL interactions for three species of abalone. In aim 2, deep mutational scanning will be utilized to explore the specific adaptations acquired by lysin and VERL that permit species specific interactions, and simultaneously test theoretical models of sexual selection. The proposed research is innovative for its combined use of proteomic and structural techniques to characterize the evolutionary history of rapidly evolving reproductive proteins. The results are expected to shed insight into the core mechanisms that mediate egg-sperm interactions in abalone, and provide foundational information towards understanding the more complex mammalian system.

 描述（由申请人提供）：自 20 世纪 80 年代以来，不孕症的发生率增加了 4%，其中高达 20% 的病例没有已知的原因，其中一个流行的假设是同源卵子和精子蛋白之间不相容，但很少有这种情况。研究受精的最佳模型仍然是海洋腹足动物鲍鱼，其中受精的第一步涉及精子蛋白之间的相互作用。赖氨酸及其蛋壳受体 VERL 作为鲍鱼蛋壳的主要成分，VERL 是一种巨大的纤维状糖蛋白，由约 22 个 ZP-N 重复序列组成，形成分子间氢键，从而形成高度稳定的保护性蛋壳。 VERL 重复序列与人类卵子外壳蛋白同源，并且可能共享相似的蛋白质。然而，驱动卵壳溶解的精确结构机制仍有待确定，为了解决受精中的这一基本问题，在目标 1 中，使用最先进的结构和蛋白质组学方法提出了两个具体目标。将用于表征三种鲍鱼的溶素-VERL 相互作用的结构基础。在目标 2 中，将利用深度突变扫描来探索溶素和 VERL 获得的特定适应，从而实现物种特异性。这项研究的创新之处在于结合使用蛋白质组学和结构技术来描述快速进化的生殖蛋白的进化史，预计这些结果将有助于深入了解介导卵子的核心机制。 -鲍鱼中精子的相互作用，并为理解更复杂的哺乳动物系统提供基础信息。