CAREER: Isoform-Dependent Redox Regulation of Actin
职业:肌动蛋白异构体依赖性氧化还原调节
基本信息
- 批准号:2146328
- 负责人:
- 金额:$ 84.82万
- 依托单位:
- 依托单位国家:美国
- 项目类别:Continuing Grant
- 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:
- 关键词:
项目摘要
This award is funded in whole or in part under the American Rescue Plan Act of 2021 (Public Law 117- 2).Actin is an essential cytoskeletal protein in eukaryotic cells that undergoes reversible monomer-to-polymer transitions. This results in a diverse array of functional configurations, ranging from actin involvement in muscle contraction to synaptic plasticity. To support such variety of functions, actin polymers are continuously disassembled to monomers and reassembled to polymers in a tightly regulated manner. This research is focused on regulation of actin dynamics by a novel reduction/oxidation (redox) mechanism. This mechanism is orchestrated by MICAL enzymes (Molecule Interacting with Cas L) that promote disassembly of actin polymers via targeted oxidation of two conserved amino acids in its sequence which, in turn, can be reversed by Methionine sulfoxide reductases (MsrB/SelR). In its polymer form, actin serves not only as a substrate of Mical but also an activator of a hydrogen peroxide production by these enzymes which potentially can lead to a broader redox signaling in health and disease. Essential cellular processes such as cell division, muscle, heart, and neuronal development require activity of MICAL, however, molecular level understanding of how actin structures in different cell types are impacted by Mical/MsrB redox mechanism is limited and will be addressed by this research. Acquired knowledge will contribute to a more complete understanding of fundamental actin-dependent cellular processes. The Broader Impacts of this work comprise a tight integration of research and education. This project will have a positive impact on development of a competitive STEM workforce, full participation of women, first generation students, and underrepresented minorities in STEM, improved STEM educator development at the level of local increased public scientific literacy via development of a free web resource. American Rescue Plan funding provides support for this investigator at a critical stage in her career.The actin cytoskeleton is indispensable for viability of eukaryotic cell. In mammals, a variety of actin-based structures are built from six different isoforms that are expressed in a cell type-specific manner. How these cytoskeletal structures are differentially regulated based on their actin isoform composition is an open fundamental question. The goal of this project is to understand how dynamics of actin isoforms are differentially regulated by a novel mechanism orchestrated by Mical and MsrB enzymes which involves site-specific oxidation/reduction of two methionines in actin’s sequence. The central hypothesis to be tested is that upon Mical-induced oxidation, actin dynamics, stability, interactions, and activation of Mical-mediated hydrogen peroxide production are actin isoform-dependent. This will be addressed by combining synthetic biology, biochemistry, biophysics, and TIRF imaging, and will allow defining the key features of actin that determine it susceptibility to Mical-induced disassembly and MrsB-driven reassembly. This knowledge will be broadly applicable and allow for prediction of the biological consequences of Mical activation based on the local actin isoform composition. The acquired knowledge will contribute to in-depth understanding of how the Mical/MsrB redox mechanism functions in different cells, tissues, and organisms.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
该奖项全部或部分由2021年美国救援计划法案(公法117- 2)资助。肌动蛋白是真核细胞中的一种重要细胞骨架蛋白,可进行可逆的单体到聚合物的转变。这导致了一系列不同的功能配置,从肌动蛋白参与肌肉收缩到突触可塑性。为了支持这样的功能多样性,肌动蛋白聚合物被连续地分解成单体,并以严格调控的方式重新组装成聚合物。这项研究的重点是通过一种新的还原/氧化(氧化还原)机制调节肌动蛋白动力学。该机制由MICAL酶(与Cas L相互作用的分子)协调,MICAL酶通过其序列中两个保守氨基酸的靶向氧化促进肌动蛋白聚合物的分解,这反过来可以被甲硫氨酸亚砜还原酶(MSRB/SelR)逆转。在其聚合物形式中,肌动蛋白不仅作为Mical的底物,而且也是这些酶产生过氧化氢的激活剂,这可能导致健康和疾病中更广泛的氧化还原信号传导。基本的细胞过程,如细胞分裂,肌肉,心脏和神经元发育需要MICAL的活性,然而,在不同细胞类型的肌动蛋白结构如何受到Mical/MsrB氧化还原机制的影响的分子水平的理解是有限的,将通过这项研究来解决。获得的知识将有助于更全面地了解基本的肌动蛋白依赖的细胞过程。这项工作的更广泛影响包括研究和教育的紧密结合。 该项目将对发展有竞争力的STEM劳动力,妇女,第一代学生和STEM中代表性不足的少数群体的充分参与,改善地方STEM教育者的发展,以及通过开发免费的网络资源提高公众科学素养产生积极影响。 美国救援计划基金在她事业的关键阶段为这位研究者提供了支持。肌动蛋白细胞骨架是真核细胞生存所不可缺少的。在哺乳动物中,各种基于肌动蛋白的结构是由六种不同的亚型构建的,这些亚型以细胞类型特异性的方式表达。这些细胞骨架结构是如何根据其肌动蛋白亚型组成进行差异调节的是一个开放的基本问题。该项目的目标是了解肌动蛋白同工型的动力学如何通过Mical和MSRB酶协调的新机制进行差异调节,该机制涉及肌动蛋白序列中两个甲硫氨酸的位点特异性氧化/还原。待检验的中心假设是,在Mical诱导的氧化后,肌动蛋白动力学、稳定性、相互作用和Mical介导的过氧化氢产生的活化是肌动蛋白亚型依赖性的。这将通过结合合成生物学、生物化学、生物物理学和TIRF成像来解决,并将允许定义肌动蛋白的关键特征,这些特征决定其对Mical诱导的拆解和MrsB驱动的重新组装的易感性。这方面的知识将是广泛适用的,并允许预测的生物学后果的Mical激活的基础上,当地的肌动蛋白亚型组成。获得的知识将有助于深入了解Mical/MSRB氧化还原机制如何在不同的细胞、组织和生物体中发挥作用。该奖项反映了NSF的法定使命,并通过使用基金会的知识价值和更广泛的影响审查标准进行评估,被认为值得支持。
项目成果
期刊论文数量(2)
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