Uncovering the substrate recognition mechanisms of the E3 ligase adaptor cereblon
揭示 E3 连接酶接头 cereblon 的底物识别机制
基本信息
- 批准号:10685519
- 负责人:
- 金额:$ 32.84万
- 依托单位:
- 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:2022-09-01 至 2026-05-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAgingAminesAmino Acid SequenceAsparagineBindingBiologicalBiological AssayBiological ProcessC-terminalCellsChemicalsClinicComplexCoupledCyclizationDataDevelopmentDipeptidesDysmyelopoietic SyndromesElementsEngineeringEnzymesEvaluationEventGenerationsGluesGlutamineHealthHematopoietic NeoplasmsHumanImidesIn VitroInvestigationKineticsLabelLibrariesLigandsMapsMeasurementModelingModificationMolecularMultiple MyelomaNeurologicPathway interactionsPatientsPeptidesPeriodicityPhysiologicalPlayPost-Translational Protein ProcessingProteinsProteomeProteomicsReaderRegulationRoleSignal TransductionSiteSpecificitySubstrate SpecificitySystemTeratogenic effectsThalidomideTherapeuticTherapeutic EffectTissue SampleUbiquitinWorkWritinganaloganti-cancerbiological systemschemoproteomicschromosome 5q lossglutarimideguided inquiryimmune modulating agentsinhibitorinsightlenalidomidemulticatalytic endopeptidase complexnovelnovel strategiesnucleophilic additionpomalidomideprotein degradationrecruitresponsesmall moleculetherapeutic developmenttissue cultureubiquitin-protein ligase
项目摘要
PROJECT SUMMARY
The immunomodulatory drugs thalidomide, lenalidomide, and pomalidomide exert their therapeutic effects by
tailoring the substrate specificity of cereblon, a component of the ubiquitin proteasome system, resulting in
altered substrate recruitment, ubiquitylation, and degradation. However, the native substrate specificity and
biological functions of cereblon are elusive, despite the conservation of cereblon across species, its association
with neurological development, and the potential impact that therapeutic engagement of cereblon would have
on these substrates and pathways. To address the urgent need for better characterization of the native role
cereblon plays in biological regulation, we undertook a novel approach to discover the substrate recognition
mechanism of cereblon. We used a targeted protein degradation approach to systematically screen
physiologically relevant ligands for functional engagement of cereblon in cells and discovered that we could
replace thalidomide with peptides bearing a C-terminal glutarimide or aspartimide, which are post-translational
modifications derived from cyclization of glutamine or asparagine, respectively. Endogenously, these C-terminal
cyclic imides may act as molecular glues to recruit substrates to cereblon by tailoring substrate recognition,
analogous to thalidomide, or may be generated directly on the substrate during protein aging and damage
response or in response to signaling events. To address these two hypotheses, we will functionally characterize
the recognition of these C-terminal cyclic imides by cereblon in cells in the context of two models: as peptide-
based metabolites that alter substrate recognition or as part of a novel degron found at the C-terminus of proteins
after protein aging or during a signaling event. We will first fully evaluate the recognition of peptide-based ligands
in the context of bifunctional degraders for targeted protein degradation to characterize the scope and
ligandability of cereblon by peptides and evaluate their ability to act as molecular glues for substrate recruitment
in a manner analogous to thalidomide and lenalidomide. Next, we will assess whether C-terminal cyclic imides
act as degrons that promote substrate recognition directly on engineered and endogenous proteins in biological
systems. To facilitate the study of these modifications, we will develop orthogonal chemical labeling strategies
to detect and map where and when these modifications occur in cells. Finally, we will investigate the formation
of these modifications in cells to characterize the conditions, pathways, and “writers” that generate the C-terminal
cyclic imides recognized by cereblon. The definition of C-terminal glutarimide and aspartimide modifications as
the key recognition elements used to recruit endogenous substrates to cereblon and the associated studies
constitutes a significant advance that will open new investigations into the biological regulation of proteins
through these post-translational modifications and the effects on these pathways during cereblon engagement
by small molecules, which will inform the use and development of therapeutics that engage cereblon in the clinic.
项目摘要
免疫调节药物沙利度胺、来那度胺和泊马度胺通过以下方式发挥其治疗作用:
定制cereblon的底物特异性,cereblon是泛素蛋白酶体系统的组分,导致
改变的底物募集、泛素化和降解。然而,天然底物特异性和
cereblon的生物学功能是难以捉摸的,尽管cereblon在物种间是保守的,它的关联
与神经系统发育的关系,以及cereblon治疗的潜在影响
在这些基质和途径上。解决更好地描述土著人作用的迫切需要
cereblon在生物调节中的作用,我们采用了一种新的方法来发现底物识别
cereblon的机制我们使用靶向蛋白降解方法系统地筛选
生理学上相关的配体的cereblon在细胞中的功能参与,并发现我们可以
用带有C-末端戊二酰亚胺或天冬酰亚胺的肽代替沙利度胺,这些肽是翻译后的
分别衍生自谷氨酰胺或天冬酰胺的环化的修饰。内源性地,这些C末端
环状酰亚胺可以作为分子胶通过定制底物识别来将底物补充到cereblon,
类似于沙利度胺,或者可以在蛋白质老化和损伤过程中直接在底物上产生
响应或响应信号事件。为了解决这两个假设,我们将从功能上描述
在两种模型的背景下,这些C-末端环状酰亚胺在细胞中被cereblon识别:作为肽-
改变底物识别的代谢物或作为蛋白质C末端发现的新型降解决定子的一部分
在蛋白质老化之后或在信号传导事件期间。我们将首先全面评估肽基配体的识别
在用于靶向蛋白质降解的双功能降解剂的背景下,
通过肽的cereblon的可配位性,并评估它们作为底物募集的分子胶的能力
以类似于沙利度胺和来那度胺的方式。接下来,我们将评估C-末端环状酰亚胺是否
作为降解决定子,直接促进生物学中工程化和内源性蛋白质上的底物识别
系统.为了促进这些修饰的研究,我们将开发正交化学标记策略
以检测和绘制这些修饰在细胞中何时何地发生。最后,我们将研究
这些修饰在细胞中表征的条件,途径,和“作家”,产生C-末端
Cereblon识别的环状酰亚胺。C-末端戊二酰亚胺和天冬酰亚胺修饰的定义为
用于募集内源性底物到cereblon的关键识别元件及相关研究
构成了一个重大的进步,将打开新的研究,生物调节蛋白质
通过这些翻译后修饰以及在cereblon参与过程中对这些通路的影响,
这将为临床上使用cereblon的治疗方法的使用和开发提供信息。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Molecular and Structural Characterization of Lenalidomide-Mediated Sequestration of eIF3i.
- DOI:10.1021/acschembio.2c00706
- 发表时间:2022-11-18
- 期刊:
- 影响因子:4
- 作者:Lin, Zhi;Shen, Dacheng;Yang, Bo;Woo, Christina M.
- 通讯作者:Woo, Christina M.
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{{ truncateString('Christina Woo', 18)}}的其他基金
Writing and erasing O-GlcNAc on target proteins in the brain
在大脑中的目标蛋白上写入和擦除 O-GlcNAc
- 批准号:
10637668 - 财政年份:2023
- 资助金额:
$ 32.84万 - 项目类别:
Uncovering the substrate recognition mechanisms of the E3 ligase adaptor cereblon
揭示 E3 连接酶接头 cereblon 的底物识别机制
- 批准号:
10446251 - 财政年份:2022
- 资助金额:
$ 32.84万 - 项目类别:
Tools to facilitate manipulation of protein-specific glycosylation stoichiometry in cells
促进细胞中蛋白质特异性糖基化化学计量操作的工具
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10203887 - 财政年份:2019
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$ 32.84万 - 项目类别:
Tools to facilitate manipulation of protein-specific glycosylation stoichiometry in cells
促进细胞中蛋白质特异性糖基化化学计量操作的工具
- 批准号:
9814357 - 财政年份:2019
- 资助金额:
$ 32.84万 - 项目类别:
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