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Molecular Mechanisms of Copper Delivery to Mitochondrial Cytochrome c Oxidase

铜传递至线粒体细胞色素 c 氧化酶的分子机制

基本信息

批准号：
10467011
负责人：
Vishal Mahendrasingh Gohil
金额：
$ 31.18万
依托单位：
TEXAS A&M AGRILIFE RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10467011
关键词：
Address Antineoplastic Agents Binding Binding Proteins Biochemical Biochemistry Bypass Cells Client Complex Copper Cysteine Disease Disulfides Energy Metabolism Environment Enzymes Genes Genetic Growth Human Hypoxia In Vitro Inherited Investigation Knowledge Mediating Menkes Kinky Hair Syndrome Micronutrients Mitochondria Mitochondrial Diseases Mitochondrial Proteins Modeling Molecular Mutate Organ Oxidases Oxidation-Reduction Oxygen Consumption PTGS1 gene PTGS2 gene Pathway interactions Patients Play Process Production Proteins Respiration Role Site Structure Sulfhydryl Compounds Testing Therapeutic Thiol Disulfide Oxidoreductase Work Yeast Model System Yeasts base cofactor cytochrome c oxidase disulfide bond effective therapy experimental study in vivo infancy loss of function mutation member novel overexpression oxidation prevent protein protein interaction public health relevance respiratory respiratory enzyme trafficking yeast genetics

项目摘要

Modified Project Summary/Abstract Section Copper (Cu) is an essential micronutrient that acts as a catalytic cofactor for a number of enzymes including cytochrome c oxidase (CcO), a critical enzyme required for mitochondrial energy production. Cu delivery to CcO is a complex process requiring multiple proteins, and loss-of-function mutations in several of the genes encoding these proteins cause fatal infantile disorders. Currently, no effective therapy exists for these fatal disorders. This is due, in part, to our incomplete understanding of how Cu is trafficked to the mitochondria and is delivered to the Cu-containing subunits of CcO. To address this gap in our knowledge, we use complementary approaches involving yeast genetics and biochemistry to discover and characterize the novel mitochondrial proteins that facilitate Cu delivery to CcO. Using these approaches, we have found the evolutionarily conserved mitochondrial proteins Coa4 and Coa6 as new members of the mitochondrial Cu delivery pathways to CcO. Now, we aim to define the biochemical functions of Coa4 and Coa6 in the Cu delivery process. Our preliminary findings, including the structure of human COA6, have led us to hypothesize that Coa4 and Coa6 play redox roles in Cu delivery to CcO. We will test this hypothesis by determining the in vitro and in vivo redox states of Coa4- and Coa6- interacting proteins and by defining the physical basis of interaction through genetic and protein:protein interaction studies. Thus, the proposed project addresses fundamental questions in Cu delivery mechanisms to CcO.

修改项目摘要/摘要部分铜（Cu）是一种必需的微量营养素，其充当许多酶的催化辅因子，包括细胞色素c氧化酶（CcO），细胞色素c氧化酶是线粒体能量产生所需的关键酶。铜传递到CcO是一个复杂的过程，需要多种蛋白质，在编码这些蛋白质的几个基因的功能丧失突变导致致命的婴儿疾病。目前，对于这些致命的疾病没有有效的治疗方法。这在一定程度上是由于我们对Cu如何被运输到线粒体并被递送到CcO的含Cu亚基的不完全理解。为了解决我们知识中的这一差距，我们使用涉及酵母遗传学和生物化学的互补方法来发现和表征促进Cu递送至CcO的新型线粒体蛋白。使用这些方法，我们已经发现了进化上保守的线粒体蛋白CoA 4和CoA 6作为线粒体铜传递途径的新成员CcO。现在，我们的目标是确定辅酶A 4和辅酶A 6在铜输送过程中的生化功能。我们的初步研究结果，包括人类辅酶A6的结构，使我们假设辅酶A4和辅酶A6在铜传递到CcO中发挥氧化还原作用。我们将测试这一假设，通过确定在体外和体内的氧化还原状态的CoA 4和CoA 6相互作用的蛋白质，并通过定义的物理基础，通过遗传和蛋白质：蛋白质相互作用的研究。因此，拟议的项目解决了铜输送机制的CcO的基本问题。

项目成果

期刊论文数量（19）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Specific requirements of nonbilayer phospholipids in mitochondrial respiratory chain function and formation.

DOI：
10.1091/mbc.e15-12-0865
发表时间：
2016-07-15
期刊：
Molecular biology of the cell
影响因子：
3.3
作者：
Baker CD;Basu Ball W;Pryce EN;Gohil VM
通讯作者：
Gohil VM

FDX1 Is Required for the Biogenesis of Mitochondrial Cytochrome c Oxidase in Mammalian Cells.

FDX1 是哺乳动物细胞中线粒体细胞色素 c 氧化酶的生物发生所必需的。

DOI：
10.1016/j.jmb.2023.168317
发表时间：
2023
期刊：
Journal of molecular biology
影响因子：
5.6
作者：
Zulkifli,Mohammad;Okonkwo,AdrianaU;Gohil,VishalM
通讯作者：
Gohil,VishalM

Choline restores respiration in Psd1-deficient yeast by replenishing mitochondrial phosphatidylethanolamine.

DOI：
10.1016/j.jbc.2021.100539
发表时间：
2021-01
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Iadarola DM;Joshi A;Caldwell CB;Gohil VM
通讯作者：
Gohil VM

A genome-wide copper-sensitized screen identifies novel regulators of mitochondrial cytochrome c oxidase activity.

全基因组铜敏化筛选鉴定出线粒体细胞色素 c 氧化酶活性的新型调节因子。

DOI：
10.1016/j.jbc.2021.100485
发表时间：
2021-01
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Garza NM;Griffin AT;Zulkifli M;Qiu C;Kaplan CD;Gohil VM
通讯作者：
Gohil VM

Yeast homologs of human MCUR1 regulate mitochondrial proline metabolism.

DOI：
10.1038/s41467-020-18704-1
发表时间：
2020-09-25
期刊：
Nature communications
影响因子：
16.6
作者：
Zulkifli M;Neff JK;Timbalia SA;Garza NM;Chen Y;Watrous JD;Murgia M;Trivedi PP;Anderson SK;Tomar D;Nilsson R;Madesh M;Jain M;Gohil VM
通讯作者：
Gohil VM