Department of Ophthalmology and Visual Sciences, University of Utah Health Sciences Center, Salt Lake City, UT 84132, USA.
FEBS Lett. 2013 Aug 2;587(15):2430-4. doi: 10.1016/j.febslet.2013.06.012. Epub 2013 Jun 20.
Human blue and mouse S-opsin are prone to aggregation in the absence of 11-cis-retinal, which underlie the rapid cone degeneration in human patients and animal models of Leber congenital amaurosis (LCA). By in silico analysis and domain swapping experiments, we show that a Phe-rich region in short-wavelength sensitive (SWS) opsins, but not in medium/long-wavelength sensitive opsins, is responsible for SWS opsin aggregation. Mutagenesis studies suggest that Phe residues in this region are critical in mediating protein aggregation. Fusing the Phe-rich region of SWS opsins to GFP causes the latter to aggregate. Our findings suggest that new therapeutics can be designed to disrupt the Phe-rich region in preventing cone degeneration due to S-opsin aggregation in LCA.
人类蓝色视蛋白和小鼠 S-opsin 在缺乏 11-顺式视黄醛的情况下容易聚集，这是导致人类患者和莱伯先天性黑蒙（LCA）动物模型中快速视锥细胞变性的基础。通过计算机分析和结构域交换实验，我们表明短波长敏感（SWS）视蛋白中的富含苯丙氨酸区域，但不是中/长波长敏感视蛋白中的富含苯丙氨酸区域，负责 SWS 视蛋白聚集。突变研究表明，该区域的苯丙氨酸残基在介导蛋白质聚集中起关键作用。将 SWS 视蛋白中的富含苯丙氨酸区域与 GFP 融合会导致后者聚集。我们的研究结果表明，可以设计新的治疗方法来破坏富含苯丙氨酸的区域，以防止由于 LCA 中 S-opsin 聚集导致的视锥细胞变性。
