Chemical Biology Approaches to Studying Collagen IV Stability
研究胶原蛋白 IV 稳定性的化学生物学方法
基本信息
- 批准号:10723042
- 负责人:
- 金额:$ 43.57万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-01 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:AffinityAnabolismAnimalsAutomobile DrivingBasement membraneBindingBiochemicalBiogenesisBiological AssayBiologyBlindnessC-terminalCartilageCataractCell LineCell secretionCellsCharacteristicsChemicalsCollagenCollagen GeneCollagen Type IVCorneal dystrophyDefectDiagnosisDiseaseDrug CombinationsEhlers-Danlos SyndromeEndoplasmic ReticulumExtracellular MatrixExtracellular SpaceFamilyFutureGeneticGenetic DiseasesGlaucomaGluesGoalsGould SyndromeHearingHereditary nephritisIndividualKidneyLaboratoriesLengthMethodsMicrophthalmosMissense MutationModelingMolecularMuscle WeaknessMutagenesisMutationN-terminalNonsense MutationOrganOsteogenesis ImperfectaPathway interactionsPenetrancePersonsPharmaceutical PreparationsPhenotypePhysiologic Intraocular PressurePlayPost-Translational Protein ProcessingProcessProtein EngineeringProteinsProtomerRecombinantsRoleSignaling MoleculeSiteSkinSymptomsSystemTechnologyTestingTissuesVariantWorkautosomebiochemical modelbonecell motilitydesigndrug discoverydrug-like compoundexperienceeye drynessgene therapyhigh throughput screeningimprovedinnovationmechanical propertiesmouse modelpreclinical studyrare genetic disorderself assemblyskeletalsmall moleculetooltriple helix
项目摘要
PROJECT SUMMARY/ABSTRACT
Collagens are essential components of the extra-cellular matrix and basement membranes, where they serve to
maintain tissue integrity, facilitate cell migration, and organize signaling molecules. To achieve these activities,
mature collagens are secreted from cells as stable trimers. Each collagen protomer is composed of three
domains: a C-terminal, non-collagenous (NC1) domain, a collagen domain and an N-terminal domain (NTD).
Newly synthesized collagen proteins undergo a unique “C-to-N” folding pathway in the endoplasmic reticulum
(ER), in which individual, C-terminal NC1 domains first assemble into trimers prior to collagen triple helix
formation. Collagens are also heavily modified by post-translational modifications (PTMs) prior to secretion of
mature collagen trimers to the extracellular space.
Collagen-associated disorders (CADs), such as Osteogenesis Imperfecta, Ehlers-Danlos syndrome (EDS) and
Alport’s syndrome, are relatively common (1:5,000 to 1:10,000) genetic diseases that most commonly arise from
mutations in collagen genes. Because of the key roles played by collagens in ocular tissues, vision loss is a
common feature of CADs. For example, ocular dysgenesis is a feature of Gould Syndrome, a rare genetic
disorder associated with mutations in type IV collagen a1 (COL4A1) and type IV collagen a2 (COL4A2). We
propose that stabilizing NC1 interactions with genetic (e.g., gene therapy) or chemical (e.g., molecular glues)
approaches is a potential, new way to treat Gould Syndrome. Specifically, we envision that stabilization of
COL4A1-COL4A2 contacts will partially overcome the impact of missense or nonsense mutations by driving
assembly of type IV collagen [a1a2a2(IV)] heterotrimers. To explore this idea, we used computational protein
design to create a “stabilizer” variant, COL4A2S150W, in which residue packing at the COL4A2-COL4A1 interface
is optimized. Indeed, we found that expression of COL4A2S150W enhanced biogenesis of collagen [a1a2a2(IV)]
by 7-fold in a quantitative, cell-based model. Now, we are poised to (Specific Aim 1) screen Gould Syndrome-
associated mutations to reveal which ones can be partially corrected in cell-based and biochemical models.
Then, we will (Specific Aim 2) conduct high throughput chemical screens, which leverage our innovative, cell-
based assays and “stabilizer” COL4A2S150W tool, to identify drug-like molecules that promote collagen
[a1a2a2(IV)] biogenesis. Together, we expect these studies to reveal the relationship between NC1 affinity and
collagen secretion in models of Gould Syndrome. We also hope to produce starting points for new Gould
Syndrome treatments and provide a framework for potentially treating other CADs.
项目总结/摘要
胶原蛋白是细胞外基质和基底膜的重要组成部分,它们的作用是
维持组织完整性、促进细胞迁移和组织信号分子。为了实现这些活动,
成熟胶原蛋白以稳定的三聚体形式从细胞中分泌。每个胶原蛋白原体由三个
结构域:C-末端非胶原(NC 1)结构域、胶原结构域和N-末端结构域(NTD)。
新合成的胶原蛋白在内质网中经历独特的“C-to-N”折叠途径
(ER)其中单个的C-末端NC 1结构域首先组装成三聚体,然后组装成胶原三螺旋。
阵胶原蛋白也在分泌前通过翻译后修饰(PTM)进行大量修饰。
成熟的胶原三聚体进入细胞外空间。
胶原相关疾病(CAD),如成骨不全、埃勒斯-当洛斯综合征(EDS)和
Alport综合征是相对常见的(1:5,000至1:10,000)遗传性疾病,最常见的原因是
胶原基因的突变。由于胶原蛋白在眼组织中起着关键作用,视力丧失是一种严重的疾病。
CAD的共同特点。例如,眼发育不全是古尔德综合征的一个特征,古尔德综合征是一种罕见的遗传病,
与IV型胶原α 1(COL 4A 1)和IV型胶原α 2(COL 4A 2)突变相关的疾病。我们
提出稳定NC 1与遗传(例如,基因疗法)或化学疗法(例如,分子胶)
这种方法是治疗古尔德综合征的一种潜在的新方法。具体而言,我们设想,
COL 4A 1-COL 4A 2接触将部分克服错义或无义突变的影响,
IV型胶原蛋白[a1 a2 a2(IV)]异源三聚体的组装。为了探索这个想法,我们使用了计算蛋白质
设计以创建“稳定剂”变体,COL 4A 2S 150 W,其中在COL 4A 2-COL 4A 1界面处的残留物包装
是优化的。事实上,我们发现COL 4A 2S 150 W的表达增强了胶原蛋白[a1 a2 a2(IV)]的生物合成。
在定量的细胞模型中增加了7倍。现在,我们准备(具体目标1)筛选古尔德综合征-
相关的突变,以揭示哪些可以在基于细胞和生物化学模型中部分纠正。
然后,我们将(具体目标2)进行高通量化学筛选,利用我们的创新,细胞-
基于分析和“稳定剂”COL 4A 2S 150 W工具,以确定促进胶原蛋白的药物样分子
[a1 a2 a2(IV)]生物成因。总之,我们希望这些研究能够揭示NC 1亲和力与
古尔德综合征模型中的胶原蛋白分泌。我们也希望能为新古尔德制作起点
综合征的治疗,并提供了一个框架,可能治疗其他CAD。
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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Jason E Gestwicki其他文献
Exploration of the Binding Determinants of Protein Phosphatase 5 (PP5) Reveals a Chaperone-Independent Activation Mechanism.
蛋白磷酸酶 5 (PP5) 结合决定因素的探索揭示了一种不依赖分子伴侣的激活机制。
- DOI:
- 发表时间:
2024 - 期刊:
- 影响因子:4.8
- 作者:
Shweta Devi;Annemarie Charvat;Zoe Millbern;Nelson Vinueza;Jason E Gestwicki - 通讯作者:
Jason E Gestwicki
Jason E Gestwicki的其他文献
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{{ truncateString('Jason E Gestwicki', 18)}}的其他基金
Research Training in Chemistry and Chemical Biology
化学和化学生物学研究培训
- 批准号:
10410908 - 财政年份:2022
- 资助金额:
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Research Training in Chemistry and Chemical Biology
化学和化学生物学研究培训
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10624303 - 财政年份:2022
- 资助金额:
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Differential Scanning Fluorimetry (DSF) Methods for Studying Protein Stability
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10626847 - 财政年份:2021
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10462611 - 财政年份:2021
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Activation of the 20S Proteasome to Normalize Tau Homeostasis
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Chemical Probes and Chaperone-Accelerated Turnover of Tau
化学探针和分子伴侣加速 Tau 蛋白的周转
- 批准号:
8519207 - 财政年份:2012
- 资助金额:
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增强 HIV 蛋白酶抑制剂的天然产物方法
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8416319 - 财政年份:2012
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