Use of Xenopus a system to study the trafficking,function and structure of IRBP

利用Xenopus系统研究IRBP的运输、功能和结构

基本信息

项目摘要

Project Summary Interphotoreceptor-retinoid binding protein (IRBP) is expressed by the retina, and its absence leads to photoreceptor degeneration in transgenic mice. As the major soluble component of the interphotoreceptor matrix (IPM), has access to the cone and rod outer segments, apical RPE surface, and M¿ller cell villi, The mechanism for IRBP's complex function in protecting retinoids from isomeric and oxidative degradation while targeting their delivery/release between the above cells during the visual cycle is poorly understood. X-ray crystal structure of one of IRBP's four "modules" shows two hydrophobic ligand-binding domains. Separate conserved surface charged domains could function to bind to components of the cell surface or matrix. Progress in this field has been hampered by the lack of a system that could allow study IRPB's function from the molecular to cellular-physiological levels. Here, we take advantage of Xenopus as a system to understand the structure, trafficking and cellular interactions required for its complex function. Our review of the literature, and findings have lead to our Hypothesis that IRBP protects retinol from oxidation within a specialized "hydrophobic cavity", and binding in cavity is allosterically regulated by separate conserved surface charged, and fatty acid binding domains. This hypothesis will be evaluated through 3 complementary specific aims: Aim 1. To determine the mechanism for IRBP mediated clearance of retinol from the outer segments. We hypothesize that IRBP interacts through a receptor to clear retinol from the outer segments. This will be addressed through physiological studies monitoring the removal of all-trans retinol from the outer segments, and studies aimed at uncovering binding partners for IRBP in the retina. We anticipate that the Asp1081Asn mutant in human rRP disrupts this interaction. Aim 2. To determine if IRBP's functions as an antioxidant in the retina. We anticipate that IRBP can retard rod outer segment lipid peroxidation, and preserve the oxidative state of retinoids within the interphotoreceptor matrix. A goal will be to determine the mechanism of this activity. Aim 3. To determine the X-ray crystal structure of full-length Xenopus IRBP. This research will lead to the X-ray crystal structure of both the holo- and apo-IRBP structures. We anticipate that that all-trans and 11- cis retinol bind within a specialized hydrophobic cavity. We predict that ligand binding to the site is allosterically regulated by fatty acid binding in the bba-fold (shallow cleft), Finally disruption of a salt bridge between highly conserved Asp and Arg residues has structural consequences to the nearby retinol binding site.
项目概要 感光细胞间视黄醇结合蛋白(IRBP)由视网膜表达,其缺失会导致 转基因小鼠的光感受器变性。作为光感受器间的主要可溶性成分 基质(IPM),可以进入锥体和杆体的外节、顶端 RPE 表面和米勒细胞绒毛, IRBP 保护类维生素A免受异构体和氧化降解的复杂功能的机制 在视觉周期期间,它们在上述细胞之间的靶向传递/释放尚不清楚。 X射线 IRBP 的四个“模块”之一的晶体结构显示出两个疏水性配体结合域。分离 保守的表面带电域可以起到与细胞表面或基质的成分结合的作用。 由于缺乏可以从以下方面研究 IRPB 功能的系统,该领域的进展受到阻碍: 分子到细胞生理水平。在这里,我们利用 Xenopus 作为一个系统来了解 其复杂功能所需的结构、运输和细胞相互作用。 我们对文献的回顾和研究结果得出了我们的假设:IRBP 可以保护视黄醇免受 在专门的“疏水腔”内进行氧化,并且在腔中的结合受到变构调节 分离保守的表面带电结构域和脂肪酸结合结构域。该假设将被评估 通过 3 个互补的具体目标: 目标 1. 确定 IRBP 介导的视黄醇从外节段清除的机制。 我们假设 IRBP 通过受体相互作用,清除外部节段的视黄醇。这将是 通过监测外节中全反式视黄醇去除情况的生理学研究来解决, 以及旨在发现视网膜中 IRBP 结合伙伴的研究。我们预计 Asp1081Asn 人类 rRP 的突变破坏了这种相互作用。 目标 2. 确定 IRBP 是否在视网膜中发挥抗氧化剂的作用。我们预计 IRBP 可以延缓 视杆外节脂质过氧化,并保持光感受器间类维生素A的氧化状态 矩阵。目标是确定该活动的机制。 目标 3. 确定全长非洲爪蟾 IRBP 的 X 射线晶体结构。这项研究将导致 Holo-和apo-IRBP结构的X射线晶体结构。我们预计全反式和 11- 顺式视黄醇结合在专门的疏水腔内。我们预测配体与该位点的结合是变构的 受 bba 折叠(浅裂口)中脂肪酸结合的调节,最终破坏高度之间的盐桥 保守的天冬氨酸和精氨酸残基对附近的视黄醇结合位点具有结构影响。

项目成果

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FEDERICO GONZALEZ-FERNANDEZ其他文献

FEDERICO GONZALEZ-FERNANDEZ的其他文献

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{{ truncateString('FEDERICO GONZALEZ-FERNANDEZ', 18)}}的其他基金

Use of Xenopus a system to study the trafficking,function and structure of IRBP
利用Xenopus系统研究IRBP的运输、功能和结构
  • 批准号:
    7797727
  • 财政年份:
    2009
  • 资助金额:
    --
  • 项目类别:
Use of Xenopus a system to study the trafficking,function and structure of IRBP
利用Xenopus系统研究IRBP的运输、功能和结构
  • 批准号:
    7920050
  • 财政年份:
    2009
  • 资助金额:
    --
  • 项目类别:
Use of Xenopus a system to study the trafficking,function and structure of IRBP
利用Xenopus系统研究IRBP的运输、功能和结构
  • 批准号:
    8391575
  • 财政年份:
    2009
  • 资助金额:
    --
  • 项目类别:
MODULE--TRANSGENIC ANIMALS
模块--转基因动物
  • 批准号:
    6949308
  • 财政年份:
    2005
  • 资助金额:
    --
  • 项目类别:
IRBP--STRUCTURE/FUNCTION
IRBP--结构/功能
  • 批准号:
    2861435
  • 财政年份:
    1993
  • 资助金额:
    --
  • 项目类别:
IRBP--STRUCTURE AND FUNCTION
IRBP--结构和功能
  • 批准号:
    2163048
  • 财政年份:
    1993
  • 资助金额:
    --
  • 项目类别:
IRBP: Structure and Function
IRBP:结构和功能
  • 批准号:
    6949916
  • 财政年份:
    1993
  • 资助金额:
    --
  • 项目类别:
IRBP: Structure and Function
IRBP:结构和功能
  • 批准号:
    7087719
  • 财政年份:
    1993
  • 资助金额:
    --
  • 项目类别:
IRBP--STRUCTURE AND FUNCTION
IRBP--结构和功能
  • 批准号:
    2444346
  • 财政年份:
    1993
  • 资助金额:
    --
  • 项目类别:
IRBP--STRUCTURE AND FUNCTION
IRBP--结构和功能
  • 批准号:
    2163047
  • 财政年份:
    1993
  • 资助金额:
    --
  • 项目类别:

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