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

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/文摘

项目成果

期刊论文数量(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

Adhesin Amyloid Biology
粘附素淀粉样蛋白生物学
  • 批准号:
    10726038
  • 财政年份:
    2023
  • 资助金额:
    $ 43.57万
  • 项目类别:
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:
    $ 43.57万
  • 项目类别:
Research Training in Chemistry and Chemical Biology
化学和化学生物学研究培训
  • 批准号:
    10624303
  • 财政年份:
    2022
  • 资助金额:
    $ 43.57万
  • 项目类别:
Differential Scanning Fluorimetry (DSF) Methods for Studying Protein Stability
研究蛋白质稳定性的差示扫描荧光 (DSF) 方法
  • 批准号:
    10626847
  • 财政年份:
    2021
  • 资助金额:
    $ 43.57万
  • 项目类别:
Differential Scanning Fluorimetry (DSF) Methods for Studying Protein Stability
研究蛋白质稳定性的差示扫描荧光 (DSF) 方法
  • 批准号:
    10462611
  • 财政年份:
    2021
  • 资助金额:
    $ 43.57万
  • 项目类别:
Differential Scanning Fluorimetry (DSF) Methods for Studying Protein Stability
研究蛋白质稳定性的差示扫描荧光 (DSF) 方法
  • 批准号:
    10184149
  • 财政年份:
    2021
  • 资助金额:
    $ 43.57万
  • 项目类别:
Activation of the 20S Proteasome to Normalize Tau Homeostasis
激活 20S 蛋白酶体使 Tau 稳态正常化
  • 批准号:
    9329344
  • 财政年份:
    2016
  • 资助金额:
    $ 43.57万
  • 项目类别:
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:
    $ 43.57万
  • 项目类别:
Natural Product-Inspired Method for Enhancing HIV Protease Inhibitors
增强 HIV 蛋白酶抑制剂的天然产物方法
  • 批准号:
    8259867
  • 财政年份:
    2012
  • 资助金额:
    $ 43.57万
  • 项目类别:
Natural Product-Inspired Method for Enhancing HIV Protease Inhibitors
增强 HIV 蛋白酶抑制剂的天然产物方法
  • 批准号:
    8416319
  • 财政年份:
    2012
  • 资助金额:
    $ 43.57万
  • 项目类别:

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骨骼合成代谢过程中骨-脂肪相互作用
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    2021
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促进NAD合成代谢以延长寿命
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