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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Bibliographic Details
Published in:The Journal of biological chemistry 2005-03, Vol.280 (11), p.10721-10730
Main Authors: Wu, Winco W.H., Wong, Julie P., Kast, Juergen, Molday, Robert S.
Format: Article
Language:English
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
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Summary: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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M413117200