RHODOPSIN MISFOLDING IN RETINITIS PIGMENTOSA

色素性视网膜炎中的视紫红质错误折叠

• 批准号: 6138206
• 负责人: H. GOBIND KHORANA
• 金额: $ 25.12万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6138206
• 关键词: SDS polyacrylamide gel electrophoresis; aminoacid; animal tissue; chemical binding; chromophore; disulfide bond; gene mutation; immunoaffinity chromatography; immunofluorescence technique; membrane proteins; molecular rearrangement; nucleic acid sequence; phosphorylation; physical model; protein disulfide isomerase; protein folding; protein sequence; protein structure function; retinitis pigmentosa; rhodopsin; tissue /cell culture; transducin; visual phototransduction

DESCRIPTION (Adapted from applicant's abstract): Mutations in the rhodopsin gene are associated with and are the most common cause of RP. More than 70 mutations, mostly single amino acid changes have been identified in rhodopsin and these have been observed in all the three, intradiscal, transmembrane and cytoplasmic domains. Work on the in vivo folding pathway of rhodopsin from this laboratory has demonstrated that a variety of site-specific mutations in the P23H, G188R in the intradiscal domain as well as the mutation L125R in the transmembrane helix C, which have been identified in RP, have been shown to cause misfolding of the corresponding opsins. The questions to be asked in the present research proposal are the following: (1) how many of the known RP mutations in rhodopsin actually cause partial or total misfolding and what are their overall consequences in visual transduction; (2) what is the precise chemical nature of the abnormal covalent linkage, a disulfide bond, that characterizes misfolding in RP mutants; and (3) can rearrangement of the wrong disulfide bond to the normal disulfide bond, that characterizes the correctly folded opsin, be achieved in vitro with possible significance in vivo.

描述（改编自申请人的摘要）：视紫红质突变 基因与 RP 相关，并且是 RP 的最常见原因。 70多个 突变，主要是单个氨基酸的变化已在 视紫红质和这些已在所有三个椎间盘内观察到， 跨膜结构域和细胞质结构域。 研究体内折叠途径 该实验室的视紫红质已证明多种 椎间盘内 P23H、G188R 的位点特异性突变 作为跨膜螺旋 C 中的突变 L125R，已被 RP 中鉴定的，已被证明会导致相应的错误折叠 视蛋白。 本研究计划要提出的问题是 以下：(1) 视紫红质中已知的 RP 突变实际上有多少 导致部分或全部错误折叠以及它们的总体后果是什么 视觉传导； (2) 异常的确切化学性质是什么 共价键，一种二硫键，是 RP 中错误折叠的特征 突变体； (3)可以将错误的二硫键重排成正常的二硫键 二硫键，表征正确折叠的视蛋白，被实现 体外可能具有体内意义。