Amino-terminal acetylation of proteins in mammalian biology and disease

哺乳动物生物学和疾病中蛋白质的氨基末端乙酰化

• 批准号: 10059999
• 负责人: GHOLSON LYON
• 金额: $ 3.52万
• 依托单位: INSTITUTE FOR BASIC RES IN DEV DISABIL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10059999
• 关键词: Acetylation; Acetyltransferase; Affect; Alleles; Alzheimer' s Disease; Binding; Biology; Cardiac; Cardiac development; Cardiomegaly; Cell Culture Techniques; Cell Line; Cells; Communities; Complex; Congenital Disorders; Congenital Heart Defects; Coupled; Craniofacial Abnormalities; Cryptorchidism; Derivation procedure; Development; Developmental Delay Disorders; Disease; Dissection; Embryo; Enzymes; Family; Functional disorder; Genes; Genetic Diseases; Grant; Health; Heart failure; Histologic; Human; Huntington Disease; Laboratories; Link; Lysine; Malignant Neoplasms; Mass Spectrum Analysis; Missense Mutation; Modification; Molecular Biology; Muscle hypotonia; Mutation; N-terminal; Names; Neurodegenerative Disorders; Parkinson Disease; Pathway interactions; Patients; Phenotype; Physiology; Post-Translational Protein Processing; Protein Acetylation; Proteins; Rare Diseases; Reporting; Role; Syndrome; System; Utah; boys; congenital heart disorder; de novo mutation; human model; in vivo Model; insight; knock-down; mouse model; neurodevelopment; prevent; protein function; tumor progression

PROJECT SUMMARY Although the scientific community has made substantial progress in elucidating the function of many genes, much remains unknown, particularly concerning the diversity introduced into proteins with co- and post- translational modifications. One such modification is amino-terminal acetylation (NTA), which is considerably understudied, with very few reports on the mammalian N-terminome. Protein acetylation occurs both at lysine residues within proteins (lysine acetylation or N-ε-acetylation) and at the N-terminus of proteins (Nt-acetylation or N--acetylation). Protein Nt-acetylation is among the most common modifications of eukaryotic proteins and is carried out by N-terminal acetyltransferases (NATs). The knockdown phenotypes of human NATs in cell culture suggest that protein NTA is an essential modification in human cells to maintain proliferation, but functional insights and mammalian in vivo models are lacking. Understanding of a general role for NTA remains elusive, and only a few examples in which NTA affects protein function, complex formation, activity, or stability are known. My laboratory discovered and characterized the first genetic disease coupled to N-terminal acetylation (NTA) of proteins, involving a missense mutation in the X-linked gene NAA10; we named this rare disease Ogden syndrome (OS) in honor of the hometown (Ogden, Utah), where the first family we identified with OS lived. The affected boys have a distinct combination of craniofacial anomalies, hypotonia, global developmental delays, cryptorchidism, cardiac anomalies, and cardiomegaly. We and others then found more than a dozen families with overlapping phenotypes with additional mutations in NAA10 in this pathway; we also reported recently that de novo mutations in NAA15, encoding a binding partner for NAA10, are involved in congenital heart defects and/or neurodevelopment. This finding is consistent with the range of cardiac anomalies and neurodevelopmental delays seen in OS (now more broadly known as NAA10-related disorders). As part of our long-term focus on the mechanistic dissection of NTA, over the next five years, we will focus on detailed phenotyping of humans with mutations in the pathway, alongside a systems-level study of unique mouse models, including conditional alleles, using histologic and functional approaches to provide the first mechanistic insights into the role of NTA in cardiac development and mammalian physiology. We will also continue our analysis of a newly identified enzyme in the pathway, which we propose compensates for and prevents embryonic lethality in humans and mouse models with mutations in NAA10. This R35 grant will enable the study of the molecular biology and pathophysiology associated with NAA10- and NAA15-related disorders and the NTA pathway, as part of a sustained effort to understand the role of NTA in mammalian biology. These studies will be a critical step toward revealing the role of NTA in human health and disease, as NTA has been linked to cancer progression and neurodegenerative diseases, including Parkinson’s, Alzheimer’s, and Huntington’s diseases.

项目概要 尽管科学界在阐明许多基因的功能方面取得了实质性进展， 还有很多未知，特别是关于通过共和和后引入蛋白质的多样性。 翻译修饰之一是氨基末端乙酰化（NTA），这是相当重要的。 尚未得到充分研究，有关哺乳动物 N 末端乙酰化的报道很少。 蛋白质内的残基（赖氨酸乙酰化或 N-ε-乙酰化）和蛋白质 N 末端的残基（Nt-乙酰化） 或 N-α-乙酰化）。蛋白质 Nt-乙酰化是真核蛋白质最常见的修饰之一。 由 N 末端乙酰转移酶 (NAT) 进行 细胞培养中人类 NAT 的敲低表型。 表明 NTA 蛋白是人类细胞维持增殖的重要修饰，但功能性 对于 NTA 的一般作用仍缺乏深入的了解和哺乳动物体内模型。 NTA 影响蛋白质功能、复合物形成、活性或稳定性的例子仅有少数。 我的实验室发现并鉴定了第一种与 N 末端乙酰化 (NTA) 相关的遗传病 蛋白质，涉及 X 连锁基因 NAA10 的错义突变，我们将这种罕见疾病命名为 Ogden； 综合症（OS），以纪念家乡（犹他州奥格登），我们发现的第一个患有 OS 的家庭就居住在那里。 受影响的男孩具有明显的颅面异常、肌张力低下、整体发育迟缓的组合， 我们和其他人随后发现了十多个家庭有隐睾症、心脏异常和心脏肥大。 我们最近还报道了该通路中 NAA10 存在额外突变的重叠表型； NAA15 的从头突变编码 NAA10 的结合伴侣，与先天性心脏缺陷有关 这一发现与心脏异常和/或神经发育的范围一致。 OS 中出现的神经发育迟缓（现在更广泛地称为 NAA10 相关疾病）。 长期关注NTA的机理解析，未来五年，我们将重点关注详细 对具有该途径突变的人类进行表型分析，同时对独特的小鼠模型进行系统级研究， 包括条件等位基因，使用组织学和功能方法提供第一个机制见解 我们还将继续分析 NTA 在心脏发育和哺乳动物生理学中的作用。 该途径中新发现的酶，我们建议补偿并防止胚胎致死 带有 NAA10 突变的人类和小鼠模型将能够进行该分子的研究。 与 NAA10 和 NAA15 相关疾病以及 NTA 途径相关的生物学和病理生理学，如 这些研究是了解 NTA 在哺乳动物生物学中的作用的持续努力的一部分。 由于 NTA 与癌症有关，因此朝着揭示 NTA 在人类健康和疾病中的作用迈出了一步 进展和神经退行性疾病，包括帕金森病、阿尔茨海默病和亨廷顿病。