Elements of the Ca2+ signal transduction pathway of Toxoplasma gondii

弓形虫Ca2信号转导通路的元件

基本信息

批准号：
10154355
负责人：
Silvia N Moreno
金额：
$ 18.88万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-14 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10154355
关键词：
Active Sites Address Adhesives Amino Acid Motifs Amino Acids Antiparasitic Agents Automobile Driving Bacterial Adhesins Binding Binding Proteins Biochemical Biological Biological Process Biotin CALM1 gene Calcium Calcium Binding Calcium Signaling Calcium ion Calcium-Binding Proteins Calmodulin Cell membrane Cell physiology Cells Clinical Complement Complex Dimerization Disease EF Hand Motifs EF-Hand Domain Elements Epitopes Eukaryota Eukaryotic Cell Event Future Goals Growth Individual Infection Invaded Ion Channel Ions Knowledge Label Ligase Lytic Phase Medical Molecular Molecular Conformation Mutation Organism PAWR protein Parasites Pathogenesis Pathology Pathway interactions Play Proteins Reporting Role Shapes Signal Pathway Signal Transduction Signal Transduction Pathway Signaling Molecule Structure Toxoplasma gondii Toxoplasmosis Transducers Virulence Work cell motility chemotherapy extracellular insight knock-down novel obligate intracellular parasite pathogen protein protein interaction response sensor

项目摘要

Toxoplasma gondii is an obligate intracellular parasite that replicates inside host cells. T. gondii belongs to the Apicomplexan phylum which also includes a number of pathogens of medical and veterinary relevance. The clinical manifestations of these diseases are a direct result of the growth of parasites within host cells. Replication and dissemination within the host are essential mechanisms by which T. gondii causes disease. T. gondii engages in multiple rounds of a lytic cycle, which consists of attachment and secretion of unique adhesins, invasion of host cells, replication, egress and search of another host cell to invade. Almost all of these biological functions are triggered by an increase in cytosolic free calcium (Ca2+), followed by stimulation of signaling cascades that are poorly characterized. Many of the transducing elements downstream to Ca2+ are either not known or have not been characterized or their interaction with other elements in the signaling cascade is not clear. Discovery and characterization of new signaling elements is highly significant because Ca2+ signaling forms part of the signaling mechanisms by which T. gondii and other related pathogens, cause disease. In addition, essential parasite calcium signaling players can be developed as targets for anti-parasitic chemotherapy.Fluctuations of the cytosolic Ca2+ concentration regulate a variety of cellular functions in all eukaryotes. Ca2+ signaling starts by an increase in cytosolic Ca2+ that results from influx from the extracellular milieu or release from intracellular stores. The information encoded in transient Ca2+ signals is deciphered by various intracellular Ca2+ binding proteins (CBPs) that convert the signals into a wide variety of biochemical changes. CBPs bind Ca2+ through specific domains like the EF-hand domains composed of EF-hands. Calmodulin (CaM), with four EF hands plays a central role in Ca2+ signaling and it is the main mechanism by which Ca2+ signals are amplified to the scale of proteins and is transduced into biological responses. Binding of Ca2+ triggers a dramatic change in CaM shape favoring its interaction with target proteins resulting in diverse effects like relieve of autoinhibition, changes in domains structures, remodeling of active sites and also protein dimerization. In this proposal we aim at discovering new Ca2+ signaling players by exploring T. gondii CaM (TgCaM) binding sensors. Almost nothing is known about TgCaM and its downstream sensors, which most likely play essential roles in T. gondii by transducing information from Ca2+ signals. It is likely that some of the targets/sensors have been identified but the mechanistic basis for their activation, potentially by binding to TgCaM has not been shown. We believe that our work will lead to the discovery of novel bridging elements in the Ca2+ signaling cascade offering potentially novel chemotherapeutic targets. Additionally, the discovery of new protein players within established signaling pathways has the potential to generate novel insight into the early origins of complex signaling networks.

弓形虫是一种专性细胞内寄生虫，可在宿主细胞内复制。刚地弓形虫属于顶复门，还包括许多与医学和兽医相关的病原体。这这些疾病的临床表现是宿主细胞内寄生虫生长的直接结果。复制和在宿主内传播是弓形虫引起疾病的重要机制。弓形虫参与多轮裂解循环，其中包括独特粘附素的附着和分泌，宿主细胞的入侵、复制、出口和寻找另一个宿主细胞来入侵。几乎所有这些生物细胞质游离钙 (Ca2+) 的增加会触发功能，然后刺激信号传导级联的特征很差。 Ca2+ 下游的许多转导元件要么不是已知或尚未表征，或者它们与信号级联中其他元件的相互作用尚未确定清除。新信号传导元件的发现和表征非常重要，因为 Ca2+ 信号传导构成弓形虫和其他相关病原体引起疾病的信号机制的一部分。在此外，重要的寄生虫钙信号传导因子可以被开发为抗寄生虫的靶标化疗。胞浆 Ca2+ 浓度的波动调节所有细胞的多种功能真核生物。 Ca2+ 信号传导始于胞质 Ca2+ 的增加，而胞质 Ca2+ 是由细胞外流入引起的环境或从细胞内储存释放。瞬态 Ca2+ 信号中编码的信息可通过以下方式破译各种细胞内 Ca2+ 结合蛋白 (CBP)，可将信号转化为多种生化信号变化。 CBP 通过特定结构域（如由 EF-hand 组成的 EF-hand 结构域）结合 Ca2+。钙调蛋白 (CaM) 具有四个 EF 手，在 Ca2+ 信号传导中发挥核心作用，它的主要机制是其中 Ca2+ 信号被放大到蛋白质的范围并转化为生物反应。绑定 Ca2+ 引发 CaM 形状的巨大变化，有利于其与靶蛋白的相互作用，从而产生多种缓解自身抑制、结构域结构变化、活性位点和蛋白质重塑等效应二聚化。在本提案中，我们的目标是通过探索刚地弓形虫 CaM 来发现新的 Ca2+ 信号传导因子 (TgCaM) 结合传感器。关于 TgCaM 及其下游传感器几乎一无所知，很可能通过从 Ca2+ 信号转导信息，在弓形虫中发挥重要作用。很可能其中一些目标/传感器已被识别，但其激活的机制基础，可能是通过结合 TgCaM 尚未显示。我们相信我们的工作将导致发现新的桥接元素 Ca2+ 信号级联提供了潜在的新型化疗靶点。此外，还发现已建立的信号通路中的新蛋白质参与者有可能产生新的见解复杂信号网络的早期起源。