Abstract
The photoreceptor-specific tetraspanin glycoprotein RDS (retinal degeneration slow) is associated with many forms of inherited retinal disease. RDS shares features in common with other tetraspanin proteins, including the existence of a large intradiscal D2 loop containing several cysteines. While these cysteines are used only for intramolecular disulfide bonds in most tetraspanins, RDS expresses a seventh, unpaired cysteine (C150) used for intermolecular disulfide bonding in the formation of large RDS oligomers. To study oligomerization-dependent vs. oligomerization-independent RDS functions in rods, we generated a transgenic mouse line harboring a point mutation that replaces this Cys with Ser (C150S), leading to the expression of an RDS protein that cannot form intermolecular disulfide bonds. The mouse opsin promoter (MOP) was used to direct C150S RDS expression specifically in rods in these transgenic mice (MOP-T). Here we report improvement in scotopic ERGs in MOP-T/rds +/– mice (compared to non-transgenic rds +/– controls) and the appearance of malformed outer segments (OSs) in MOP-T mice that do not express native RDS (MOP-T/rds –/–). These results suggest that while normal OS structure and function require RDS oligomerization, some RDS function is retained in the absence of C150. Since one of the functions of other tetraspanin proteins is to promote assembly of a membrane microdomain known as the “tetraspanin web”, future studies may investigate whether assembly of this web is one of RDS’s oligomerization-independent functions.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Arikawa K, Molday LL, Molday RS et al (1992) Localization of peripherin/rds in the disk membranes of cone and rod photoreceptors: relationship to disk membrane morphogenesis and retinal degeneration. J Cell Biol 116:659–667
Chakraborty D, Ding XQ, Conley SM et al (2008a) Differential requirements for Rds intermolecular disulfide-linked oligomerization in rods versus cones. Hum Mol Genet 18:797–808
Chakraborty D, Ding XQ, Fliesler SJ et al (2008b) Outer segment oligomerization of Rds: evidence from mouse models and subcellular fractionation. Biochemistry 47:1144–1156
Connell GJ, Molday RS (1990) Molecular cloning, primary structure, and orientation of the vertebrate photoreceptor cell protein peripherin in the rod outer segment disk membrane. Biochemistry 29:4691–4698
Delaguillaumie A, Lagaudriere-Gesbert C, Popoff MR et al (2002) Rho GTPases link cytoskeletal rearrangements and activation processes induced via the tetraspanin CD82 in T lymphocytes. J Cell Sci 115:433–443
Farjo R, Naash MI (2006) The role of rds in outer segment morphogenesis and human retinal disease. Ophthalmic Genet 27:117–122
Goldberg AF, Loewen CJ, Molday RS (1998) Cysteine residues of photoreceptor peripherin/rds: role in subunit assembly and autosomal dominant retinitis pigmentosa. Biochemistry 37: 680–685
Hemler ME (2001) Specific tetraspanin functions. J Cell Biol 155:1103–1107
Hemler ME (2003) Tetraspanin proteins mediate cellular penetration, invasion, and fusion events and define a novel type of membrane microdomain. Annu Rev Cell Dev Biol 19:397–422
Lagaudriere-Gesbert C, Lebel-Binay S, Hubeau C et al (1998) Signaling through the tetraspanin CD82 triggers its association with the cytoskeleton leading to sustained morphological changes and T cell activation. Eur J Immunol 28:4332–4344
Levy S, Shoham T (2005) Protein-protein interactions in the tetraspanin web. Physiology (Bethesda) 20:218–224
Li C, Ding XQ, O’Brien J et al (2003) Molecular characterization of the skate peripherin/rds gene: relationship to its orthologues and paralogues. Invest Ophthalmol Vis Sci 44:2433–2441
Loewen CJ, Molday RS (2000) Disulfide-mediated oligomerization of Peripherin/Rds and Rom-1 in photoreceptor disk membranes. Implications for photoreceptor outer segment morphogenesis and degeneration. J Biol Chem 275:5370–5378
Loewen CJ, Moritz OL, Tam BM et al (2003) The role of subunit assembly in peripherin-2 targeting to rod photoreceptor disk membranes and retinitis pigmentosa. Mol Biol Cell 14:3400–3413
Molday RS, Hicks D, Molday L (1987) Peripherin. A rim-specific membrane protein of rod outer segment discs. Invest Ophthalmol Vis Sci 28:50–61
Moritz OL, Peck A, Tam BM (2002) Xenopus laevis red cone opsin and Prph2 promoters allow transgene expression in amphibian cones, or both rods and cones. Gene 298:173–182
Naash MI, Ding XQ, Li C et al (2003) Peripherin/rds in skate retina. Adv Exp Med Biol 533:377–383
Serru V, Le Naour F, Billard M et al (1999) Selective tetraspan-integrin complexes (CD81/alpha4beta1, CD151/alpha3beta1, CD151/alpha6beta1) under conditions disrupting tetraspan interactions. Biochem J 340(Pt 1):103–111
Shigeta M, Sanzen N, Ozawa M et al (2003) CD151 regulates epithelial cell-cell adhesion through PKC- and Cdc42-dependent actin cytoskeletal reorganization. J Cell Biol 163:165–176
Stipp CS, Kolesnikova TV, Hemler ME (2003) Functional domains in tetraspanin proteins. Trends Biochem Sci 28:106–112
Travis GH, Sutcliffe JG, Bok D (1991) The retinal degeneration slow (rds) gene product is a photoreceptor disc membrane-associated glycoprotein. Neuron 6:61–70
Wrigley JD, Ahmed T, Nevett CL et al (2000) Peripherin/rds influences membrane vesicle morphology. Implications for retinopathies. J Biol Chem 275:13191–13194
Wu XR, Medina JJ, Sun TT (1995) Selective interactions of UPIa and UPIb, two members of the transmembrane 4 superfamily, with distinct single transmembrane-domained proteins in differentiated urothelial cells. J Biol Chem 270:29752–29759
Yauch RL, Berditchevski F, Harler MB et al (1998) Highly stoichiometric, stable, and specific association of integrin alpha3beta1 with CD151 provides a major link to phosphatidylinositol 4-kinase, and may regulate cell migration. Mol Biol Cell 9:2751–2765
Acknowledgments
The monoclonal antibodies for this study (1D4) were generously shared with us by Dr. Robert Molday, University of British Columbia. The authors would like to thank Rasha Makkia for her excellent technical assistance with the transgenic animals. This study was supported by grants from the National Institutes of Health (EY10609 & EY018656 to MIN; EY007361 to SJF; Core Grant for Vision Research EY12190 to MIN), the Foundation Fighting Blindness (MIN), the Knights Templar Eye Research Foundation (DC) and a departmental Unrestricted Grant from Research to Prevent Blindness (SJF). Dr. Naash is the recipient of a Research to Prevent Blindness James S. Adams Scholar Award. Dr. Fliesler is the recipient of a Research to Prevent Blindness Senior Scientist Award.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2010 Springer Science+Business Media, LLC
About this chapter
Cite this chapter
Chakraborty, D., Conley, S.M., Fliesler, S.J., Naash, M.I. (2010). The Function of Oligomerization-Incompetent RDS in Rods. In: Anderson, R., Hollyfield, J., LaVail, M. (eds) Retinal Degenerative Diseases. Advances in Experimental Medicine and Biology, vol 664. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-1399-9_5
Download citation
DOI: https://doi.org/10.1007/978-1-4419-1399-9_5
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4419-1398-2
Online ISBN: 978-1-4419-1399-9
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)