RHODOPSIN MISFOLDING IN RETINITIS PIGMENTOSA

描述(摘自申请人的摘要)：视紫红质的突变 基因与RP相关，也是RP最常见的原因。超过70人 突变，主要是单一氨基酸的变化，已在 视紫红质和这些都在所有三个椎间盘内观察到， 跨膜区和细胞质结构域。体内折叠途径的研究进展 这个实验室的视紫红质已经证明了各种 盘内区P23H、G188R的位点特异性突变 作为跨膜螺旋C上的突变L125R，它们已经被 在RP中发现，已证明会导致相应的错误折叠 奥辛斯。本研究提案中将提出的问题是 以下是：(1)已知的视紫红质RP突变中有多少 导致部分或全部折叠错误以及它们在 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，表征RP中的错误折叠 突变体；以及(3)可以将错误的二硫键重排为正常的二硫键 二硫键，这是正确折叠的视蛋白的特征 在体外具有可能的体内意义。

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.