J Bernard Heymann , Camasamudram Vijayasarathy , Robert N. Fariss , Paul A. Sieving
{"title":"视黄裂素分子结构的研究进展及生物学功能的研究","authors":"J Bernard Heymann , Camasamudram Vijayasarathy , Robert N. Fariss , Paul A. Sieving","doi":"10.1016/j.preteyeres.2022.101147","DOIUrl":null,"url":null,"abstract":"<div><p><span><span><span><span>Retinoschisin (RS1) is a secreted protein that is essential for maintaining integrity of the retina. Numerous mutations in RS1 cause X-linked </span>retinoschisis (XLRS), a progressive degeneration of the retina that leads to </span>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 </span>synaptic transmission<span>. 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 </span></span>clinical evaluation<span><span><span><span>. 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. </span>Sequence homology indicates a </span>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 </span>disulfides<span><span>. 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 </span>extracellular matrix proteins<span>. Alternatively, RS1 may influence fluid regulation via interaction with membrane proteins<span> 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.</span></span></span></span></p></div>","PeriodicalId":21159,"journal":{"name":"Progress in Retinal and Eye Research","volume":null,"pages":null},"PeriodicalIF":18.6000,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10185713/pdf/","citationCount":"5","resultStr":"{\"title\":\"Advances in understanding the molecular structure of retinoschisin while questions remain of biological function\",\"authors\":\"J Bernard Heymann , Camasamudram Vijayasarathy , Robert N. Fariss , Paul A. Sieving\",\"doi\":\"10.1016/j.preteyeres.2022.101147\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p><span><span><span><span>Retinoschisin (RS1) is a secreted protein that is essential for maintaining integrity of the retina. Numerous mutations in RS1 cause X-linked </span>retinoschisis (XLRS), a progressive degeneration of the retina that leads to </span>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 </span>synaptic transmission<span>. 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 </span></span>clinical evaluation<span><span><span><span>. 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. </span>Sequence homology indicates a </span>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 </span>disulfides<span><span>. 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 </span>extracellular matrix proteins<span>. Alternatively, RS1 may influence fluid regulation via interaction with membrane proteins<span> 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.</span></span></span></span></p></div>\",\"PeriodicalId\":21159,\"journal\":{\"name\":\"Progress in Retinal and Eye Research\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":18.6000,\"publicationDate\":\"2023-07-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10185713/pdf/\",\"citationCount\":\"5\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Progress in Retinal and Eye Research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S1350946222001070\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"OPHTHALMOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Progress in Retinal and Eye Research","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1350946222001070","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"OPHTHALMOLOGY","Score":null,"Total":0}
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.
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.