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RS1, a Discoidin Domain-containing Retinal Cell Adhesion Protein Associated with X-linked Retinoschisis, Exists as a Novel Disulfide-linked Octamer
RS1, also known as retinoschisin, is an extracellular protein that plays a crucial role in the cellular organization of the retina. Mutations in RS1 are responsible for X-linked retinoschisis, a common, early-onset macular degeneration in males that results in a splitting of the inner layers of the...
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| Published in: | The Journal of biological chemistry 2005-03, Vol.280 (11), p.10721-10730 |
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| container_issue | 11 |
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| container_title | The Journal of biological chemistry |
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| creator | Wu, Winco W.H. Wong, Julie P. Kast, Juergen Molday, Robert S. |
| description | RS1, also known as retinoschisin, is an extracellular protein that plays a crucial role in the cellular organization of the retina. Mutations in RS1 are responsible for X-linked retinoschisis, a common, early-onset macular degeneration in males that results in a splitting of the inner layers of the retina and severe loss in vision. RS1 is assembled and secreted from photoreceptors and bipolar cells as a homo-oligomeric protein complex. Each subunit consists of a 157-amino acid discoidin domain flanked by two small segments of 39 and 5 amino acids. To begin to understand how the structure of RS1 relates to its role in retinal cell adhesion and X-linked retinoschisis, we have determined the subunit organization and disulfide bonding pattern of RS1 by SDS gel electrophoresis, velocity sedimentation, and mass spectrometry. Our results indicate that RS1 exists as a novel octamer in which the eight subunits are joined together by Cys59-Cys223 intermolecular disulfide bonds. Subunits within the octamer are further organized into dimers mediated by Cys40-Cys40 bonds. These cysteines lie just outside the discoidin domain indicating that these flanking segments primarily function in the octamerization of RS1. Within the discoidin domain, two cysteine pairs (Cys63-Cys219 and Cys110-Cys142) form intramolecular disulfide bonds that are important in protein folding, and one cysteine (Cys83) exists in its reduced state. Because mutations that disrupt subunit assembly cause X-linked retinoschisis, the assembly of RS1 into a disulfide-linked homo-octamer appears to be critical for its function as a retinal cell adhesion protein. |
| doi_str_mv | 10.1074/jbc.M413117200 |
| format | article |
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Mutations in RS1 are responsible for X-linked retinoschisis, a common, early-onset macular degeneration in males that results in a splitting of the inner layers of the retina and severe loss in vision. RS1 is assembled and secreted from photoreceptors and bipolar cells as a homo-oligomeric protein complex. Each subunit consists of a 157-amino acid discoidin domain flanked by two small segments of 39 and 5 amino acids. To begin to understand how the structure of RS1 relates to its role in retinal cell adhesion and X-linked retinoschisis, we have determined the subunit organization and disulfide bonding pattern of RS1 by SDS gel electrophoresis, velocity sedimentation, and mass spectrometry. Our results indicate that RS1 exists as a novel octamer in which the eight subunits are joined together by Cys59-Cys223 intermolecular disulfide bonds. Subunits within the octamer are further organized into dimers mediated by Cys40-Cys40 bonds. These cysteines lie just outside the discoidin domain indicating that these flanking segments primarily function in the octamerization of RS1. Within the discoidin domain, two cysteine pairs (Cys63-Cys219 and Cys110-Cys142) form intramolecular disulfide bonds that are important in protein folding, and one cysteine (Cys83) exists in its reduced state. Because mutations that disrupt subunit assembly cause X-linked retinoschisis, the assembly of RS1 into a disulfide-linked homo-octamer appears to be critical for its function as a retinal cell adhesion protein.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M413117200</identifier><identifier>PMID: 15644328</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Amino Acid Sequence ; Ammonium Sulfate - chemistry ; Ammonium Sulfate - pharmacology ; Animals ; Blotting, Western ; Cattle ; Cell Adhesion ; Cell Line ; Chromosomes, Human, X - genetics ; Cysteine - chemistry ; Detergents - pharmacology ; Dimerization ; Discoidin Domain Receptors ; Disulfides - chemistry ; DNA, Complementary - metabolism ; Electrophoresis, Polyacrylamide Gel ; Eye Proteins - chemistry ; Eye Proteins - physiology ; Humans ; Immunoprecipitation ; Mass Spectrometry ; Models, Biological ; Molecular Sequence Data ; Mutation ; Peptide Mapping ; Peptides - chemistry ; Protein Binding ; Protein Conformation ; Protein Folding ; Protein Structure, Tertiary ; Protein Transport ; Receptor Protein-Tyrosine Kinases - chemistry ; Receptors, Mitogen - chemistry ; Retina - chemistry ; Retina - cytology ; Retina - metabolism ; Retinoschisis - genetics ; Retinoschisis - metabolism ; Trypsin - chemistry</subject><ispartof>The Journal of biological chemistry, 2005-03, Vol.280 (11), p.10721-10730</ispartof><rights>2005 © 2005 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c442t-3320bf2f841ccc25dffbe9bed2e52979b6ac6d5e9dbae9a44a5c50807f0299643</citedby><cites>FETCH-LOGICAL-c442t-3320bf2f841ccc25dffbe9bed2e52979b6ac6d5e9dbae9a44a5c50807f0299643</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,786,790,27957,27958</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15644328$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wu, Winco W.H.</creatorcontrib><creatorcontrib>Wong, Julie P.</creatorcontrib><creatorcontrib>Kast, Juergen</creatorcontrib><creatorcontrib>Molday, Robert S.</creatorcontrib><title>RS1, a Discoidin Domain-containing Retinal Cell Adhesion Protein Associated with X-linked Retinoschisis, Exists as a Novel Disulfide-linked Octamer</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>RS1, also known as retinoschisin, is an extracellular protein that plays a crucial role in the cellular organization of the retina. Mutations in RS1 are responsible for X-linked retinoschisis, a common, early-onset macular degeneration in males that results in a splitting of the inner layers of the retina and severe loss in vision. RS1 is assembled and secreted from photoreceptors and bipolar cells as a homo-oligomeric protein complex. Each subunit consists of a 157-amino acid discoidin domain flanked by two small segments of 39 and 5 amino acids. To begin to understand how the structure of RS1 relates to its role in retinal cell adhesion and X-linked retinoschisis, we have determined the subunit organization and disulfide bonding pattern of RS1 by SDS gel electrophoresis, velocity sedimentation, and mass spectrometry. Our results indicate that RS1 exists as a novel octamer in which the eight subunits are joined together by Cys59-Cys223 intermolecular disulfide bonds. Subunits within the octamer are further organized into dimers mediated by Cys40-Cys40 bonds. These cysteines lie just outside the discoidin domain indicating that these flanking segments primarily function in the octamerization of RS1. Within the discoidin domain, two cysteine pairs (Cys63-Cys219 and Cys110-Cys142) form intramolecular disulfide bonds that are important in protein folding, and one cysteine (Cys83) exists in its reduced state. Because mutations that disrupt subunit assembly cause X-linked retinoschisis, the assembly of RS1 into a disulfide-linked homo-octamer appears to be critical for its function as a retinal cell adhesion protein.</description><subject>Amino Acid Sequence</subject><subject>Ammonium Sulfate - chemistry</subject><subject>Ammonium Sulfate - pharmacology</subject><subject>Animals</subject><subject>Blotting, Western</subject><subject>Cattle</subject><subject>Cell Adhesion</subject><subject>Cell Line</subject><subject>Chromosomes, Human, X - genetics</subject><subject>Cysteine - chemistry</subject><subject>Detergents - pharmacology</subject><subject>Dimerization</subject><subject>Discoidin Domain Receptors</subject><subject>Disulfides - chemistry</subject><subject>DNA, Complementary - metabolism</subject><subject>Electrophoresis, Polyacrylamide Gel</subject><subject>Eye Proteins - chemistry</subject><subject>Eye Proteins - physiology</subject><subject>Humans</subject><subject>Immunoprecipitation</subject><subject>Mass Spectrometry</subject><subject>Models, Biological</subject><subject>Molecular Sequence Data</subject><subject>Mutation</subject><subject>Peptide Mapping</subject><subject>Peptides - chemistry</subject><subject>Protein Binding</subject><subject>Protein Conformation</subject><subject>Protein Folding</subject><subject>Protein Structure, Tertiary</subject><subject>Protein Transport</subject><subject>Receptor Protein-Tyrosine Kinases - chemistry</subject><subject>Receptors, Mitogen - chemistry</subject><subject>Retina - chemistry</subject><subject>Retina - cytology</subject><subject>Retina - metabolism</subject><subject>Retinoschisis - genetics</subject><subject>Retinoschisis - metabolism</subject><subject>Trypsin - chemistry</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><recordid>eNqFkUFv1DAQhS0EokvhyhH5gDg1i-3YSXxcbUtBKhQVkHqzHHvSTEniEnvb8jv4w3jZRT0hLEsjS997M55HyEvOlpzV8u1165YfJS85rwVjj8iCs6YsSsUvH5MFY4IXWqjmgDyL8ZrlIzV_Sg64qqQsRbMgvy6-8CNq6TFGF9DjRI_DaHEqXJhSrjhd0QtIONmBrmEY6Mr3EDFM9PMcEmR-FWNwaBN4eoepp5fFgNP3_PojC9H1GDEe0ZN7jClSmy_9FG5h2PbcDB16-Ks4d8mOMD8nTzo7RHixr4fk27uTr-v3xdn56Yf16qxwUopUlKVgbSe6RnLnnFC-61rQLXgBSuhat5V1lVegfWtBWymtcoo1rO6Y0LqS5SF5s_O9mcOPDcRkxryF_Ek7QdhEU9WKaSXVf0FeN6Jhuszgcge6OcQ4Q2duZhzt_NNwZrZ5mZyXecgrC17tnTftCP4B3weUgdc7oMer_g5nMC0G18NockfD-dZV8Iw1Owzyvm4RZhMdwuTAZ4lLxgf81wi_AWMGsP8</recordid><startdate>20050318</startdate><enddate>20050318</enddate><creator>Wu, Winco W.H.</creator><creator>Wong, Julie P.</creator><creator>Kast, Juergen</creator><creator>Molday, Robert S.</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>7X8</scope></search><sort><creationdate>20050318</creationdate><title>RS1, a Discoidin Domain-containing Retinal Cell Adhesion Protein Associated with X-linked Retinoschisis, Exists as a Novel Disulfide-linked Octamer</title><author>Wu, Winco W.H. ; Wong, Julie P. ; Kast, Juergen ; Molday, Robert S.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c442t-3320bf2f841ccc25dffbe9bed2e52979b6ac6d5e9dbae9a44a5c50807f0299643</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Amino Acid Sequence</topic><topic>Ammonium Sulfate - chemistry</topic><topic>Ammonium Sulfate - pharmacology</topic><topic>Animals</topic><topic>Blotting, Western</topic><topic>Cattle</topic><topic>Cell Adhesion</topic><topic>Cell Line</topic><topic>Chromosomes, Human, X - genetics</topic><topic>Cysteine - chemistry</topic><topic>Detergents - pharmacology</topic><topic>Dimerization</topic><topic>Discoidin Domain Receptors</topic><topic>Disulfides - chemistry</topic><topic>DNA, Complementary - metabolism</topic><topic>Electrophoresis, Polyacrylamide Gel</topic><topic>Eye Proteins - chemistry</topic><topic>Eye Proteins - physiology</topic><topic>Humans</topic><topic>Immunoprecipitation</topic><topic>Mass Spectrometry</topic><topic>Models, Biological</topic><topic>Molecular Sequence Data</topic><topic>Mutation</topic><topic>Peptide Mapping</topic><topic>Peptides - chemistry</topic><topic>Protein Binding</topic><topic>Protein Conformation</topic><topic>Protein Folding</topic><topic>Protein Structure, Tertiary</topic><topic>Protein Transport</topic><topic>Receptor Protein-Tyrosine Kinases - chemistry</topic><topic>Receptors, Mitogen - chemistry</topic><topic>Retina - chemistry</topic><topic>Retina - cytology</topic><topic>Retina - metabolism</topic><topic>Retinoschisis - genetics</topic><topic>Retinoschisis - metabolism</topic><topic>Trypsin - chemistry</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wu, Winco W.H.</creatorcontrib><creatorcontrib>Wong, Julie P.</creatorcontrib><creatorcontrib>Kast, Juergen</creatorcontrib><creatorcontrib>Molday, Robert S.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wu, Winco W.H.</au><au>Wong, Julie P.</au><au>Kast, Juergen</au><au>Molday, Robert S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>RS1, a Discoidin Domain-containing Retinal Cell Adhesion Protein Associated with X-linked Retinoschisis, Exists as a Novel Disulfide-linked Octamer</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2005-03-18</date><risdate>2005</risdate><volume>280</volume><issue>11</issue><spage>10721</spage><epage>10730</epage><pages>10721-10730</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><notes>ObjectType-Article-2</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-1</notes><notes>content type line 23</notes><notes>ObjectType-Article-1</notes><notes>ObjectType-Feature-2</notes><abstract>RS1, also known as retinoschisin, is an extracellular protein that plays a crucial role in the cellular organization of the retina. Mutations in RS1 are responsible for X-linked retinoschisis, a common, early-onset macular degeneration in males that results in a splitting of the inner layers of the retina and severe loss in vision. RS1 is assembled and secreted from photoreceptors and bipolar cells as a homo-oligomeric protein complex. Each subunit consists of a 157-amino acid discoidin domain flanked by two small segments of 39 and 5 amino acids. To begin to understand how the structure of RS1 relates to its role in retinal cell adhesion and X-linked retinoschisis, we have determined the subunit organization and disulfide bonding pattern of RS1 by SDS gel electrophoresis, velocity sedimentation, and mass spectrometry. Our results indicate that RS1 exists as a novel octamer in which the eight subunits are joined together by Cys59-Cys223 intermolecular disulfide bonds. Subunits within the octamer are further organized into dimers mediated by Cys40-Cys40 bonds. These cysteines lie just outside the discoidin domain indicating that these flanking segments primarily function in the octamerization of RS1. Within the discoidin domain, two cysteine pairs (Cys63-Cys219 and Cys110-Cys142) form intramolecular disulfide bonds that are important in protein folding, and one cysteine (Cys83) exists in its reduced state. Because mutations that disrupt subunit assembly cause X-linked retinoschisis, the assembly of RS1 into a disulfide-linked homo-octamer appears to be critical for its function as a retinal cell adhesion protein.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>15644328</pmid><doi>10.1074/jbc.M413117200</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | The Journal of biological chemistry, 2005-03, Vol.280 (11), p.10721-10730 |
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| source | PubMed (Medline); BACON - Elsevier - GLOBAL_SCIENCEDIRECT-OPENACCESS |
| subjects | Amino Acid Sequence Ammonium Sulfate - chemistry Ammonium Sulfate - pharmacology Animals Blotting, Western Cattle Cell Adhesion Cell Line Chromosomes, Human, X - genetics Cysteine - chemistry Detergents - pharmacology Dimerization Discoidin Domain Receptors Disulfides - chemistry DNA, Complementary - metabolism Electrophoresis, Polyacrylamide Gel Eye Proteins - chemistry Eye Proteins - physiology Humans Immunoprecipitation Mass Spectrometry Models, Biological Molecular Sequence Data Mutation Peptide Mapping Peptides - chemistry Protein Binding Protein Conformation Protein Folding Protein Structure, Tertiary Protein Transport Receptor Protein-Tyrosine Kinases - chemistry Receptors, Mitogen - chemistry Retina - chemistry Retina - cytology Retina - metabolism Retinoschisis - genetics Retinoschisis - metabolism Trypsin - chemistry |
| title | RS1, a Discoidin Domain-containing Retinal Cell Adhesion Protein Associated with X-linked Retinoschisis, Exists as a Novel Disulfide-linked Octamer |
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