Mechanism behind blindness linked to excess glutamylation

失明背后的机制与过量谷氨酰化有关

• 批准号: 10314856
• 负责人: Rawaa Aljammal
• 金额: $ 4.6万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-10 至 2023-08-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10314856
• 关键词: Affinity; Animal Model; Animals; Biological; Biology; Blindness; Carboxypeptidase; Carrier Proteins; Cells; Chemicals; Cilia; Cleaved cell; Cone; Data; Defect; Development; Disease; Electroretinography; Enzymes; Event; Family; Family member; Fellowship; Foundations; Functional disorder; Future; GKLF protein; GTP-Binding Proteins; Genetic; Glutamates; Goals; Health; Human; Immunohistochemistry; Immunoprecipitation; Impairment; Inherited; Knowledge; Link; Mass Spectrum Analysis; Measures; Mediating; Modification; Molecular; Monitor; Morphology; Mus; Mutation; Neurons; Opsin; Photoreceptors; Play; Post-Translational Protein Processing; Proteins; Research; Research Personnel; Retina; Retinal Cone; Retinitis Pigmentosa; Rhodopsin; Rod; Role; Set protein; Signal Pathway; Signal Transduction; Structural Protein; Structure; Sushi Domain; Testing; Training; Transmission Electron Microscopy; Tubulin; Ubiquitination; anterograde transport; career; design; immunocytochemistry; improved; insight; member; mouse model; mutant; novel; novel strategies; novel therapeutics; overexpression; photoreceptor degeneration; protein transport; response; retinal rods; skills; success; transcription factor; tyrosyltubulin ligase

Abstract Post-translational modification of proteins play an important role in increasing the complexity and functional diversity of limited set of proteins expressed in the cell. One such interesting and highly significant chemical modification is glutamylation. Protein glutamylation is a post-translational modification (PTM) that adds glutamate to one of the glutamic residues in the C terminus of the protein. Protein Glutamylation is dynamic and controlled by repertoire of enzymes, tubulin tyrosine ligase-Like (TTLLs) that add glutamyl group, and by another family of enzymes called cytosolic carboxypeptidase (CCPs or AGBLs) that cleaves the glutamate. Mutation in one member of deglutamylase family, AGBL5 is linked to inherited blindness in humans. While glutamylation is thought to aid in trafficking of proteins, the mechanism behind the blindness linked to excess glutamylation in not known. This proposal aims to investigate the consequences of excess glutamylation in the rod and cone photoreceptors with a mouse model that lacks AGBL5. This fellowship will help reach my long-term goal of understanding mechanisms behind diseases that afflict humans. The findings from this study will advance our understanding of the mechanism underlying the genetic blindness and human health.

摘要 蛋白质翻译后修饰在增加蛋白质的复杂性和功能性方面起着重要的作用 细胞中表达的有限蛋白质组的多样性。一种如此有趣和重要的化学物质 修饰是谷氨酰化。蛋白质谷氨酰化是一种翻译后修饰（PTM）， 连接到蛋白质C末端的一个谷氨酸残基上。蛋白质的谷氨酸化是动态的和受控的 通过添加谷氨酰基团的微管蛋白酪氨酸连接酶样（TTLL）的所有酶，以及通过另一个家族的 一种叫做胞质羧肽酶（CCP或AGBL）的酶，它能裂解谷氨酸。 去谷氨酰胺酶家族成员之一AGBL 5的突变与人类遗传性失明有关。而 谷氨酰化被认为有助于蛋白质的运输，这是与过量谷氨酸有关的失明背后的机制。 谷氨酰化未知。该提案旨在研究在细胞中过量谷氨酰化的后果， 杆和锥光感受器与缺乏AGBL 5的小鼠模型。 这项研究将有助于实现我的长期目标，即了解折磨人的疾病背后的机制。 人类这项研究的发现将促进我们对遗传机制的理解。 失明和人类健康。