视黄裂素分子结构的研究进展及生物学功能的研究

IF 18.6 1区 医学 Q1 OPHTHALMOLOGY
J Bernard Heymann , Camasamudram Vijayasarathy , Robert N. Fariss , Paul A. Sieving
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引用次数: 5

摘要

视网膜裂素(RS1)是一种分泌蛋白,对维持视网膜的完整性至关重要。RS1的许多突变导致X连锁视网膜分裂症(XLRS),这是一种视网膜的渐进性变性,导致年轻男性视力下降。XLRS的一个关键表现是视网膜中空洞(囊肿)的形成和层间分离(分裂),破坏突触传递。目前还没有批准的XLRS患者治疗方法。使用腺相关病毒(AAV)载体递送RS1功能拷贝作为基因扩增治疗的一种形式的策略正在进行临床评估。为了改进治疗XLRS的治疗策略,更好地了解RS1的分泌及其分子功能至关重要。免疫荧光和免疫电子显微镜显示RS1位于光感受器内节和双极细胞的表面。序列同源性表明盘状蛋白结构域折叠,类似于许多其他具有粘附功能的蛋白质。最近的结构研究表明,RS1的三级结构是两个背靠背的八聚环,每个环由二硫化物交联。在体外观察到的更高阶结构表明,形成了跨越细胞之间距离(~100nm)的粘附基质。几项研究表明,RS1很容易与其他蛋白质结合,如钠钾ATP酶(NaK-ATP酶)和细胞外基质蛋白。或者,RS1可能通过与膜蛋白(如NaK-ATP酶)的相互作用影响液体调节,这在很大程度上是从使用碳酸酐酶抑制剂来缩小XLRS中典型的视网膜内囊肿中推断出来的。我们根据RS1的结构讨论了这些模型,并解决了理解RS1功能的困难。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Advances in understanding the molecular structure of retinoschisin while questions remain of biological function

Retinoschisin (RS1) is a secreted protein that is essential for maintaining integrity of the retina. Numerous mutations in RS1 cause X-linked retinoschisis (XLRS), a progressive degeneration of the retina that leads to vision loss in young males. A key manifestation of XLRS is the formation of cavities (cysts) in the retina and separation of the layers (schisis), disrupting synaptic transmission. There are currently no approved treatments for patients with XLRS. Strategies using adeno-associated viral (AAV) vectors to deliver functional copies of RS1 as a form of gene augmentation therapy, are under clinical evaluation. To improve therapeutic strategies for treating XLRS, it is critical to better understand the secretion of RS1 and its molecular function. Immunofluorescence and immunoelectron microscopy show that RS1 is located on the surfaces of the photoreceptor inner segments and bipolar cells. Sequence homology indicates a discoidin domain fold, similar to many other proteins with demonstrated adhesion functions. Recent structural studies revealed the tertiary structure of RS1 as two back-to-back octameric rings, each cross-linked by disulfides. The observation of higher order structures in vitro suggests the formation of an adhesive matrix spanning the distance between cells (∼100 nm). Several studies indicated that RS1 readily binds to other proteins such as the sodium-potassium ATPase (NaK-ATPase) and extracellular matrix proteins. Alternatively, RS1 may influence fluid regulation via interaction with membrane proteins such as the NaK-ATPase, largely inferred from the use of carbonic anhydrase inhibitors to shrink the typical intra-retinal cysts in XLRS. We discuss these models in light of RS1 structure and address the difficulty in understanding the function of RS1.

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来源期刊
CiteScore
34.10
自引率
5.10%
发文量
78
期刊介绍: Progress in Retinal and Eye Research is a Reviews-only journal. By invitation, leading experts write on basic and clinical aspects of the eye in a style appealing to molecular biologists, neuroscientists and physiologists, as well as to vision researchers and ophthalmologists. The journal covers all aspects of eye research, including topics pertaining to the retina and pigment epithelial layer, cornea, tears, lacrimal glands, aqueous humour, iris, ciliary body, trabeculum, lens, vitreous humour and diseases such as dry-eye, inflammation, keratoconus, corneal dystrophy, glaucoma and cataract.
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