Regulation of NRMT1 through homolog binding

通过同源物结合调节 NRMT1

基本信息

批准号：
10571563
负责人：
Christine E Schaner-Tooley
金额：
$ 3.84万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10571563
关键词：
Address Aging Bacteria Binding Binding Proteins Biochemical Biochemistry Biological Breast Cancer Cell Cell Compartmentation Cell Survival Code Complex Consensus Sequence DNA-Protein Interaction Development Disease Drug Design Enzymes Family Family member Growth Hair Histones Homologous Gene Human Knock-out Kyphosis deformity of spine Liver Fibrosis Longevity Malignant Neoplasms Mammals Memory Loss Methods Methylation Methyltransferase Mus Muscle satellite cell Myosin Light Chains N-terminal Nerve Degeneration Pattern Phenotype Physiological Play Post-Translational Protein Processing Premature aging syndrome Process Proteins Regulation Research Role Stem Cell Development Therapeutic Training Work age related amino group career cell growth experimental study loss of function migration relating to nervous system skills skin fibrosis stem cell differentiation stem cell fate therapeutic target tumorigenesis

项目摘要

Project Summary: Post-translational modification of N-terminal α-amino (Nα) groups is a highly conserved and vastly utilized process seen in all species from bacteria to mammals. Dr. Schaner Tooley pioneered the field of Nα- methylation by identifying the first two eukaryotic Nα-methyltransferases, NRMT1 and NRMT2 (also known as METTL11A and METTL11B). She went on to characterize the consensus sequence of these enzymes, identify dozens of their substrates, and show Nα-methylation regulates protein/DNA interactions. Her lab was also the first to show that, like histone PTMs, Nα-PTMs are part of a functional code. They identified the first protein known to exist in both Nα-acetyl and Nα-methyl forms, Myosin Light Chain 9 (MYL9). They demonstrated that these two Nα-PTMs create distinct proteoforms of MYL9, with unique protein binding partners, internal PTM patterns, and cell compartment-specific functions. They have also demonstrated important roles for NRMT1 in oncogenesis and aging. NRMT1 loss in breast cancer cells promotes proliferation, migration, colony formation, and xenograph growth. NRMT1 knockout in mice promotes phenotypes associated with premature aging, including, early graying and hair loss, kyphosis, skin and liver fibrosis, neurodegeneration, memory loss, and decreased lifespan. They have shown that NRMT1 regulates both neural and muscle stem cell development, and hypothesize a general role for NRMT1 in stem cell differentiation drives many of the premature aging phenotypes. They now want to 1.) expand understanding of the biochemistry of NRMT1 regulation, 2.) identify additional substrates regulated by the Nα-PTM code, and 3.) mechanistically characterize the newly discovered role for NRMT1 in stem cell fate determination. The worked proposed in this diversity supplement will address the first point and examine the regulation of NRMT1 through binding of its METTL family homologs, NRMT2 and METTL13. While it is becoming apparent that a common method of methyltransferase regulation is through complex formation with close homologs, NRMT1 is the first methyltransferase known to be opposingly regulated by two different homologs. Here we will study both the biochemistry and biological relevance of these interactions. Successful completion of these experiments will not only further the development of NRMT1 as a potential therapeutic target for human cancers and age-related disorders, but also complete Haley Parker's training in the technical and professional skills necessary to continue a research career in drug design.

项目概要： N 端 α-氨基 (Nα) 基团的翻译后修饰是高度保守且广泛利用的 Schaner Tooley 博士是 Nα- 领域的先驱。通过识别前两种真核 Nα-甲基转移酶 NRMT1 和 NRMT2（也称为 METTL11A 和 METTL11B)，她接着描述了这些酶的共有序列，鉴定了数十种底物，并表明 Nα-甲基化调节蛋白质/DNA 相互作用。他们也是第一个证明 Nα-PTM 与组蛋白 PTM 一样是功能代码的一部分的人。已知以 Nα-乙酰基和 Nα-甲基形式存在的蛋白质，肌球蛋白轻链 9 (MYL9)。证明这两个 Nα-PTM 创建了 MYL9 的独特蛋白质形式，具有独特的蛋白质结合他们还展示了合作伙伴、内部 PTM 模式和细胞区室特定功能。 NRMT1 在乳腺癌细胞的肿瘤发生和衰老中发挥重要作用。 NRMT1 敲除可促进小鼠的增殖、迁移、集落形成和异种生长。与过早衰老相关的表型，包括早白和脱发、驼背、皮肤和肝脏他们表明 NRMT1 可以调节纤维化、神经退行性变、记忆丧失和寿命缩短。神经干细胞和肌肉干细胞的发育，并关注 NRMT1 在干细胞中的一般作用分化驱动了许多过早衰老的表型，他们现在希望扩大了解。 NRMT1 调节的生物化学，2.) 识别受 Nα-PTM 代码调节的其他底物， 3.) 从机制上描述新发现的 NRMT1 在干细胞命运决定中的作用。本多样性补充中提出的工作将解决第一点并审查 NRMT1 通过其 METTL 家族同源物 NRMT2 和 METTL13 的结合而变得明显。甲基转移酶调节的常见方法是通过具有密切同系物的复合物形成， NRMT1 是已知的第一个由两种不同同源物相反调节的甲基转移酶。将研究这些相互作用的生物化学和生物学相关性。实验不仅将进一步发展 NRMT1 作为人类潜在治疗靶点癌症和与年龄相关的疾病，还完成了 Haley Parker 在技术和治疗方面的培训继续药物设计研究生涯所需的专业技能。