Substrate targeting by the Gcn5 acetyltransferase: mechanisms and consequences
Gcn5 乙酰转移酶的底物靶向:机制和后果
基本信息
- 批准号:RGPIN-2016-05015
- 负责人:
- 金额:$ 2.62万
- 依托单位:
- 依托单位国家:加拿大
- 项目类别:Discovery Grants Program - Individual
- 财政年份:2016
- 资助国家:加拿大
- 起止时间:2016-01-01 至 2017-12-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Problem: Acetylation of lysine residues is catalyzed by histone acetyltransferases (HATs) and removed by histone deacetylases (HDACs). As reflected by their names, these enzymes are best characterized as modifiers of histones. Yet, recent work from our lab and others suggests the need for a paradigm shift in how we think about acetylation as a post-translational modification. Specifically, acetylation is now thought to rival phosphorylation, with 1000s of substrates having been identified in organisms from bacteria to humans. How these substrates are chosen and what their acetylations do is not understood. Our overarching goal is to advance knowledge by determining the regulation and consequences of acetylation on a proteome-wide scale. To achieve this goal, it is necessary for us to move away from old models for acetylation based on the now-outdated assumption that histones are the only important targets.
Recent Progress: HAT and HDAC enzymes exist in large protein complexes with many subunits. Our data in yeast show that these complexes hold the key to understanding HATs and HDACs as global regulators. We focused on a complex called SAGA that contains an important HAT called Gcn5. Non-catalytic components of SAGA are usually assumed to be uniform and obligate promoters of acetylation by this HAT. Our data show that while this is true for histones, the impact of non-catalytic subunits on the acetylation of other proteins is target specific. Based on these data, we propose a new model wherein SAGA acts as a substrate selection platform. In this model, individual subunits promote or inhibit the acetylation of distinct sets of non-histone targets mediating diverse functions in the cell.
Approach and Significance: In this program, we will exploit our new model for the SAGA HAT complex to uncover mechanisms of substrate targeting and to link substrate acetylation to downstream functions. In the short term, trainees in my lab will use proteomics and functional genomics technologies in yeast to achieve three objectives. They will: (1) Determine how each subunit of SAGA impacts acetylation of Gcn5 targets; (2) identify novel genetic interactions for SAGA mutants; and (3) elucidate the function of SAGA-regulated acetylations on non-histone substrates. In the long term, we will extend what we learn from these experiments to the study of other HAT and HDAC complexes and determine how mechanisms of substrate targeting are impacted by changes to a cell’s environment. Our program will facilitate research by other labs around the world by providing the first comprehensive picture of acetylation targeting and function to date.
Training: This program will train at least 2 graduate students and up to 10 undergrads over the next 5 years. They will gain experience in proteomics, high-throughput genetics and bioinformatics. These skills will make them highly qualified for positions in both academia and industry.
问题:赖氨酸残基的乙酰化由组蛋白乙酰转移酶(HAT)催化,并由组蛋白脱乙酰酶(HDAC)去除。正如它们的名字所反映的那样,这些酶最好的特征是作为组蛋白的修饰剂。然而,我们实验室和其他人最近的工作表明,我们需要在如何看待乙酰化作为一种翻译后修饰方面进行范式转变。具体来说,乙酰化现在被认为是磷酸化的竞争对手,从细菌到人类的生物体中已经确定了1000种底物。如何选择这些底物以及它们的乙酰化作用尚不清楚。我们的总体目标是通过确定乙酰化在蛋白质组范围内的调节和后果来推进知识。为了实现这一目标,我们有必要摆脱旧的乙酰化模型,该模型基于现已过时的假设,即组蛋白是唯一重要的靶标。
最新进展:HAT和HDAC酶存在于含有许多亚基的大蛋白复合物中。我们在酵母中的数据表明,这些复合物是理解HAT和HDAC作为全球调节剂的关键。我们关注的是一个名为佐贺的复合体,它包含一个名为Gcn 5的重要HAT。佐贺的非催化组分通常被认为是通过该HAT的乙酰化的均匀和专性促进剂。我们的数据表明,虽然这对组蛋白是正确的,但非催化亚基对其他蛋白质乙酰化的影响是靶特异性的。基于这些数据,我们提出了一个新的模型,其中佐贺作为底物选择平台。在该模型中,单个亚基促进或抑制介导细胞中不同功能的不同组的非组蛋白靶标的乙酰化。
方法和意义:在这个项目中,我们将利用我们的新模型的佐贺HAT复合物,以揭示机制的底物靶向和连接底物乙酰化下游功能。在短期内,我实验室的学员将在酵母中使用蛋白质组学和功能基因组学技术来实现三个目标。他们将:(1)确定佐贺的每个亚基如何影响Gcn 5靶标的乙酰化;(2)鉴定佐贺突变体的新型遗传相互作用;(3)阐明SAGA调节的乙酰化对非组蛋白底物的功能。从长远来看,我们将从这些实验中学到的东西扩展到其他HAT和HDAC复合物的研究,并确定底物靶向机制如何受到细胞环境变化的影响。我们的计划将通过提供迄今为止乙酰化靶向和功能的第一个全面图片来促进世界各地其他实验室的研究。
培训:该项目将在未来5年内培训至少2名研究生和最多10名本科生。他们将获得蛋白质组学,高通量遗传学和生物信息学方面的经验。这些技能将使他们在学术界和工业界的职位高度合格。
项目成果
期刊论文数量(0)
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Downey, Michael其他文献
Atomic structure of the KEOPS complex: an ancient protein kinase-containing molecular machine.
- DOI:
10.1016/j.molcel.2008.10.002 - 发表时间:
2008-10-24 - 期刊:
- 影响因子:16
- 作者:
Mao, Daniel Y. L.;Neculai, Dante;Downey, Michael;Orlicky, Stephen;Haffani, Yosr Z.;Ceccarelli, Derek F.;Ho, Jenny S. L.;Szilard, Rachel K.;Zhang, Wei;Ho, Cynthia S.;Wan, Leo;Fares, Christophe;Rumpel, Sigrun;Kurinov, Igor;Arrowsmith, Cheryl H.;Durocher, Daniel;Sicheri, Frank - 通讯作者:
Sicheri, Frank
The promises of lysine polyphosphorylation as a regulatory modification in mammals are tempered by conceptual and technical challenges
- DOI:
10.1002/bies.202100058 - 发表时间:
2021-05-16 - 期刊:
- 影响因子:4
- 作者:
Baijal, Kanchi;Downey, Michael - 通讯作者:
Downey, Michael
A Broad Response to Intracellular Long-Chain Polyphosphate in Human Cells
- DOI:
10.1016/j.celrep.2020.108318 - 发表时间:
2020-10-27 - 期刊:
- 影响因子:8.8
- 作者:
Bondy-Chorney, Emma;Abramchuk, Iryna;Downey, Michael - 通讯作者:
Downey, Michael
Gcn5 and sirtuins regulate acetylation of the ribosomal protein transcription factor Ifh1.
- DOI:
10.1016/j.cub.2013.06.050 - 发表时间:
2013-09-09 - 期刊:
- 影响因子:9.2
- 作者:
Downey, Michael;Knight, Britta;Vashisht, Ajay A.;Seller, Charles A.;Wohlschlegel, James A.;Shore, David;Toczyski, David P. - 通讯作者:
Toczyski, David P.
Acetylome Profiling Reveals Overlap in the Regulation of Diverse Processes by Sirtuins, Gcn5, and Esa1
- DOI:
10.1074/mcp.m114.043141 - 发表时间:
2015-01-01 - 期刊:
- 影响因子:7
- 作者:
Downey, Michael;Johnson, Jeffrey R.;Toczyski, David P. - 通讯作者:
Toczyski, David P.
Downey, Michael的其他文献
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{{ truncateString('Downey, Michael', 18)}}的其他基金
Molecular control of non-histone protein acetylation in budding yeast
芽殖酵母非组蛋白乙酰化的分子控制
- 批准号:
RGPAS-2021-00003 - 财政年份:2022
- 资助金额:
$ 2.62万 - 项目类别:
Discovery Grants Program - Accelerator Supplements
Molecular control of non-histone protein acetylation in budding yeast
芽殖酵母非组蛋白乙酰化的分子控制
- 批准号:
RGPIN-2021-03887 - 财政年份:2022
- 资助金额:
$ 2.62万 - 项目类别:
Discovery Grants Program - Individual
Molecular control of non-histone protein acetylation in budding yeast
芽殖酵母非组蛋白乙酰化的分子控制
- 批准号:
RGPIN-2021-03887 - 财政年份:2021
- 资助金额:
$ 2.62万 - 项目类别:
Discovery Grants Program - Individual
Molecular control of non-histone protein acetylation in budding yeast
芽殖酵母非组蛋白乙酰化的分子控制
- 批准号:
RGPAS-2021-00003 - 财政年份:2021
- 资助金额:
$ 2.62万 - 项目类别:
Discovery Grants Program - Accelerator Supplements
Substrate targeting by the Gcn5 acetyltransferase: mechanisms and consequences
Gcn5 乙酰转移酶的底物靶向:机制和后果
- 批准号:
RGPIN-2016-05015 - 财政年份:2020
- 资助金额:
$ 2.62万 - 项目类别:
Discovery Grants Program - Individual
Substrate targeting by the Gcn5 acetyltransferase: mechanisms and consequences
Gcn5 乙酰转移酶的底物靶向:机制和后果
- 批准号:
RGPIN-2016-05015 - 财政年份:2019
- 资助金额:
$ 2.62万 - 项目类别:
Discovery Grants Program - Individual
Substrate targeting by the Gcn5 acetyltransferase: mechanisms and consequences
Gcn5 乙酰转移酶的底物靶向:机制和后果
- 批准号:
RGPIN-2016-05015 - 财政年份:2018
- 资助金额:
$ 2.62万 - 项目类别:
Discovery Grants Program - Individual
Substrate targeting by the Gcn5 acetyltransferase: mechanisms and consequences
Gcn5 乙酰转移酶的底物靶向:机制和后果
- 批准号:
RGPIN-2016-05015 - 财政年份:2017
- 资助金额:
$ 2.62万 - 项目类别:
Discovery Grants Program - Individual
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Substrate targeting by the Gcn5 acetyltransferase: mechanisms and consequences
Gcn5 乙酰转移酶的底物靶向:机制和后果
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Substrate targeting by the Gcn5 acetyltransferase: mechanisms and consequences
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Substrate targeting by the Gcn5 acetyltransferase: mechanisms and consequences
Gcn5 乙酰转移酶的底物靶向:机制和后果
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$ 2.62万 - 项目类别:
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Substrate targeting by the Gcn5 acetyltransferase: mechanisms and consequences
Gcn5 乙酰转移酶的底物靶向:机制和后果
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