Biochemistry, biology and diversity of Fic domains
生物化学、生物学和 Fic 领域的多样性
基本信息
- 批准号:10334464
- 负责人:
- 金额:$ 36.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-02-01 至 2025-01-31
- 项目状态:未结题
- 来源:
- 关键词:Active SitesAdenosine MonophosphateAgingBinding SitesBiochemistryBiologicalBiological ProcessBiologyCell physiologyCellsChemistryDrosophila genusEndoplasmic ReticulumEnzymesGRP78 geneGeneticGoalsGrowthHealthHomeostasisIn VitroInflammationMammalsMediatingModificationMolecularMolecular ChaperonesMolecular TargetNeurodegenerative DisordersNeuronal PlasticityNeuronsOrphanPlayProteinsRegulationRoleSodium ChlorideStressThreonineTransgenic Micecancer cellendoplasmic reticulum stressin vivointerestresponse
项目摘要
Project Summary
A variety of cellular processes are commonly subverted to encourage the proliferation of cancer cells,
one of which is the unfolded protein response (UPR) that occurs in the endoplasmic reticulum (ER).
Importantly, there is also a strong connection between UPR and inflammation or neuronal health.
Many neurodegenerative diseases and diseases of aging have connections to the UPR. We have
recently discovered a new form of BiP regulation, AMPylation by the protein Fic. We observe that Fic
adds an adenosine monophosphate (AMP) molecule to a threonine near the ATP binding site of BiP
during normal growth conditions. This modification rapidly is removed by the same enzyme Fic under
multiple ER stress-inducing conditions. We recently have shown that the regulation of BiP by Fic is
essential for maintaining neuronal homeostasis. Since our discovery of Fic domains that mediate
AMPylation, other diverse activities performed by bacterial Fic domains have been identified. These
studies have revealed the molecular plasticity of Fic domains in its ability to utilize diverse substrates.
Despite these studies, there are many different Fic proteins that remain to be characterized, both in
catalytic activity, biological function, and molecular targets. We propose three projects that will further
our understanding of the biology of Fic enzymes and the chemistry they use, both in vitro and in vivo.
First, when the ER is stressed, Fic changes from an AMPylator to a deAMPylator, and the key to this
regulation is breaking a salt bridge in Fic's active site. We want to understand the biochemistry
regulating this switch. Second, our studies with Drosophila genetics show that Fic is required for
neuronal plasticity. We are therefore interested in understanding what role Fic plays in mammalian
biology using transgenic mice. Third, there are many different Fic proteins that remain to be
characterized, both in catalytic activity, biological function, and molecular targets. We plan to
investigate these orphan Fic domains and identify their biological activities and substrates.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Kim Orth其他文献
Kim Orth的其他文献
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{{ truncateString('Kim Orth', 18)}}的其他基金
FASEB's The Microbial Pathogenesis Conference: Mechanisms of Infectious Disease
FASEB 微生物发病机制会议:传染病机制
- 批准号:
10228853 - 财政年份:2021
- 资助金额:
$ 36.9万 - 项目类别:
Biochemistry, biology and diversity of Fic domains
生物化学、生物学和 Fic 领域的多样性
- 批准号:
10550154 - 财政年份:2020
- 资助金额:
$ 36.9万 - 项目类别:
Biochemistry, biology and diversity of Fic domains
生物化学、生物学和 Fic 领域的多样性
- 批准号:
10092197 - 财政年份:2020
- 资助金额:
$ 36.9万 - 项目类别:
Proteostasis, AMPylation and the Unfolded Protein repsonse (UPR)
蛋白质稳态、AMPylation 和未折叠蛋白反应 (UPR)
- 批准号:
9229559 - 财政年份:2015
- 资助金额:
$ 36.9万 - 项目类别:
Proteostasis, AMPylation and the Unfolded Protein repsonse (UPR)
蛋白质稳态、AMPylation 和未折叠蛋白反应 (UPR)
- 批准号:
8914100 - 财政年份:2015
- 资助金额:
$ 36.9万 - 项目类别:
Analysis of newly identified adhesin used by pathogenic Gram-negative bacteria
致病性革兰氏阴性菌使用的新发现的粘附素的分析
- 批准号:
8304009 - 财政年份:2012
- 资助金额:
$ 36.9万 - 项目类别:
Analysis of newly identified adhesin used by pathogenic Gram-negative bacteria
致病性革兰氏阴性菌使用的新发现的粘附素的分析
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8518227 - 财政年份:2012
- 资助金额:
$ 36.9万 - 项目类别:
Analysis of an orchestrated cell death mediated by Vibrio parahaemolytics T3SS1
副溶血弧菌 T3SS1 介导的精心策划的细胞死亡分析
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8431443 - 财政年份:2010
- 资助金额:
$ 36.9万 - 项目类别:
Analysis of an orchestrated cell death mediated by Vibrio parahaemolytics T3SS1
副溶血弧菌 T3SS1 介导的精心策划的细胞死亡分析
- 批准号:
7867642 - 财政年份:2010
- 资助金额:
$ 36.9万 - 项目类别:
Analysis of an orchestrated cell death mediated by Vibrio parahaemolytics T3SS1
副溶血弧菌 T3SS1 介导的精心策划的细胞死亡分析
- 批准号:
8225260 - 财政年份:2010
- 资助金额:
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