Disulfide-mediated Oligomerization of Peripherin/Rds and Rom-1 in Photoreceptor Disk Membranes

Peripherin/Rds is a tetraspanning membrane protein that has been implicated in photoreceptor outer segment morphogenesis and inherited retinal degenerative diseases. Together with the structurally related protein, Rom-1, it forms a complex along the rims of rod and cone disc membranes. We have compared the oligomeric structure of these proteins from nonreduced and dithiothreitol reduced membranes by velocity sedimentation, SDS-gel electrophoresis, immunoaffinity chromatography, and chemical cross-linking. Under reducing conditions peripherin/Rds and Rom-1 existed as homomeric and heteromeric core complexes devoid of intermolecular disulfide bonds. Under nonreducing conditions core complexes associated through intermolecular disulfide bonds to form oligomers. One intermediate-size oligomer contained monomers and disulfide-linked dimers of peripherin/Rds and Rom-1, while larger oligomers consisted only of disulfide-linked peripherin/Rds dimers when analyzed on nonreducing SDS gels. Consistent with this result, disc membranes contained twice as much peripherin/Rds as Rom-1. Peripherin/Rds individually expressed in COS-1 cells also formed disulfide-linked oligomers bridged through Cys-150 residues, whereas Rom-1 showed little tendency to form oligomers. These results indicate that peripherin/Rds and Rom-1 associate noncovalently to form multisubunit core complexes. Peripherin/Rds containing core complexes interact through specific intermolecular disulfide bonds to form oligomers which may play a crucial role in photoreceptor disc morphogenesis and retinal degenerative diseases. Peripherin/Rds is a tetraspanning membrane protein that has been implicated in photoreceptor outer segment morphogenesis and inherited retinal degenerative diseases. Together with the structurally related protein, Rom-1, it forms a complex along the rims of rod and cone disc membranes. We have compared the oligomeric structure of these proteins from nonreduced and dithiothreitol reduced membranes by velocity sedimentation, SDS-gel electrophoresis, immunoaffinity chromatography, and chemical cross-linking. Under reducing conditions peripherin/Rds and Rom-1 existed as homomeric and heteromeric core complexes devoid of intermolecular disulfide bonds. Under nonreducing conditions core complexes associated through intermolecular disulfide bonds to form oligomers. One intermediate-size oligomer contained monomers and disulfide-linked dimers of peripherin/Rds and Rom-1, while larger oligomers consisted only of disulfide-linked peripherin/Rds dimers when analyzed on nonreducing SDS gels. Consistent with this result, disc membranes contained twice as much peripherin/Rds as Rom-1. Peripherin/Rds individually expressed in COS-1 cells also formed disulfide-linked oligomers bridged through Cys-150 residues, whereas Rom-1 showed little tendency to form oligomers. These results indicate that peripherin/Rds and Rom-1 associate noncovalently to form multisubunit core complexes. Peripherin/Rds containing core complexes interact through specific intermolecular disulfide bonds to form oligomers which may play a crucial role in photoreceptor disc morphogenesis and retinal degenerative diseases. rod outer segments NEM, N-ethylmaleimide phenylmethylsulfonyl fluoride enhanced chemiluminesence polyacrylamide gel electrophoresis phosphate-buffered saline Phototransduction takes place in a specialized compartment of the rod and cone photoreceptor cell called the outer segment. This compartment consists of a stack of highly ordered discs surrounded by a plasma membrane. A disc is composed of two closely spaced lamellar membranes that are fully (rods) or partially (cones) circumscribed by a hairpin membrane called the disc rim. This rim region is generally thought to play an essential role in the morphogenesis and stabilization of the outer segment, although the molecular mechanism and interactions are not yet known (1.Steinberg R.H. Fisher S.K. Anderson D.H. J. Comp. Neurol. 1980; 190: 501-508Crossref PubMed Scopus (266) Google Scholar, 2.Roof D.J. Heuser J.E. J. Cell Biol. 1982; 95: 487-500Crossref PubMed Scopus (140) Google Scholar, 3.Usukura J. Yamada E. Biomed. Res. 1981; 2: 177-193Crossref Scopus (51) Google Scholar, 4.Corless J.M. Fetter R.D. J. Comp. Neurol. 1987; 257: 24-38Crossref PubMed Scopus (29) Google Scholar). Peripherin/Rds and Rom-1 are two membrane proteins that are localized along the rim and incisures of rod and cone disc membranes (5.Molday R.S. Hicks D. Molday L.L. Invest. Ophthalmol. Vis. Sci. 1987; 28: 50-61PubMed Google Scholar, 6.Connell G. Molday R.S. Biochemistry. 1990; 29: 4691-4698Crossref PubMed Scopus (141) Google Scholar, 7.Bascom R.A. Manara S. Collins L. Molday R.S. Kalnins V.I. Neuron. 1992; 8: 1171-1184Abstract Full Text PDF PubMed Scopus (205) Google Scholar, 8.Moritz O.L. Molday R.S. Invest. Ophthalmol. Vis. Sci. 1996; 37: 352-362PubMed Google Scholar, 9.Arikawa K. Molday L.L. Molday R.S. Williams D.S. J. Cell Biol. 1992; 116: 659-667Crossref PubMed Scopus (230) Google Scholar). Peripherin/Rds is required for rod and cone outer segment morphogenesis and stabilization since rds mice homozygous for the disrupted peripherin/rds gene fail to develop outer segments and mice heterozygous for this gene defect form highly disorganized structures consisting of whorls of membranes (10.Sanyal S. Jansen H.G. Neurosci. Lett. 1981; 21: 23-26Crossref PubMed Scopus (166) Google Scholar, 11.Hawkins R.R. Jansen H.G. Sanyal S. Exp. Eye Res. 1985; 41: 701-720Crossref PubMed Scopus (158) Google Scholar, 12.Travis G.H. Brennan M.B. Danielson P.E. Kazak C.A. Sutcliffe J.G. Nature. 1989; 338: 70-73Crossref PubMed Scopus (314) Google Scholar, 13.Connell G. Bascom R.A. Molday L.L. Reid D. McInnes R.R. Molday R.S. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 723-726Crossref PubMed Scopus (237) Google Scholar, 14.Travis G.L. Groshan K.R. Lloyd M. Bok D. Neuron. 1992; 9: 113-119Abstract Full Text PDF PubMed Scopus (108) Google Scholar). Moreover, mutations in the peripherin/rds gene have been linked to a variety of inherited human retinal diseases including autosomal dominant retinitis pigmentosa, macular degeneration, and related pattern dystrophies (15.Farrar G.J. Kenna P. Jardan S.A. Kumar-Singh R. Humphries M.M. Sharp E.M. Sheils D.M. Humphries P.A. Nature. 1991; 354: 478-480Crossref PubMed Scopus (357) Google Scholar, 16.Kaijawra K. Hahn L.B. Mukai S. Travis G.H. Berson E.L. Dryja T.P. Nature. 1991; 354: 480-483Crossref PubMed Scopus (380) Google Scholar, 17.Wells J. Wroblewski J. Keen J. Inglehearn C. Jubb C. Eckstein A. Jay M. Arden G. Bhattacharya S. Fitzke F. Bird A.C. Nat. Genet. 1993; 3: 213-218Crossref PubMed Scopus (370) Google Scholar, 18.Nicols B.E. Sheffeld V.C. Vandenburgh K. Drack A.V. Kimura A.E. Stone E.M. Nat. Genet. 1993; 3: 202-207Crossref PubMed Scopus (219) Google Scholar, 19.Weleber R.G. Carr R.E. Murphey W.H. Sheffield V.C. Stone E.M. Arch. Ophthalmol. 1993; 111: 1531-1542Crossref PubMed Scopus (256) Google Scholar, 20.Saga M. Mashima Y. Akeo K. Oguchi Y. Kudoh J. Shimizu N. Hum. Genet. 1993; 92: 519-521Crossref PubMed Scopus (53) Google Scholar). Recent studies with transgenic mice have confirmed that disease-linked mutations in peripherin/rdscause outer segment disorganization and photoreceptor degeneration (21.Kedzierski W. Lloyd M. Birch D.G. Bok D. Travis G.H. Invest. Ophthalmol. Vis. Sci. 1997; 38: 498-509PubMed Google Scholar). Rom-1 plays a more ancillary role in outer segment structure. In the absence of Rom-1, characteristic rod and cone outer segments containing stacks of discs are evident (22.Clarke, G., Goldberg, A. F. X., Vidgen, D., Collins, L., Ploder, L., Schwarz, L., Molday, L. L., Rossant, J., Szél, A., Molday, R. S., Birch, D. G., and McInnes, R. R. (2000) Nat. Genet., in pressGoogle Scholar). The discs in rod cells, however, tend to be slightly longer than normal and occasionally have a disorganized appearance. Furthermore, to date mutations in the rom-1 gene have been linked only to a digenic form of autosomal dominant retinitis pigmentosa (23.Kajiwara K. Berson E.L. Dryja T.P. Science. 1994; 264: 1604-1608Crossref PubMed Scopus (612) Google Scholar, 24.Dryja T.P. Hahn L.B. Kajiwara K. Berson E.L. Invest. Ophthalmol. Vis. Sci. 1997; 38: 1972-1982PubMed Google Scholar). In this case, the disease phenotype is evident only in individuals who inherit a L185P mutation inperipherin/rds along with a rom-1 mutation. Peripherin/Rds and Rom-1 are similar in size and exhibit many common structural features (25.Molday R.S. Prog. Ret. & Eye Res. 1994; 13: 271-299Crossref Scopus (43) Google Scholar). They both contain four putative membrane spanning segments, an extended cytoplasmic C-terminal domain, a large intradiscal loop of approximately 150 amino acids that joins the third and forth transmembrane segments, and seven highly conserved cysteine residues (6.Connell G. Molday R.S. Biochemistry. 1990; 29: 4691-4698Crossref PubMed Scopus (141) Google Scholar, 7.Bascom R.A. Manara S. Collins L. Molday R.S. Kalnins V.I. Neuron. 1992; 8: 1171-1184Abstract Full Text PDF PubMed Scopus (205) Google Scholar, 8.Moritz O.L. Molday R.S. Invest. Ophthalmol. Vis. Sci. 1996; 37: 352-362PubMed Google Scholar, 26.Travis G.L. Sutcliffe J.G. Bok D. Neuron. 1991; 6: 61-70Abstract Full Text PDF PubMed Scopus Google Scholar). The of peripherin/Rds has been to membrane in a role for this in the outer segment K. S. Y. Biochemistry. 37: PubMed Scopus Google Scholar). The large intradiscal loop of however, disease mutations and to play a crucial role in interactions for disc and stabilization Molday R.S. Proc. Natl. Acad. Sci. U. S. A. 1996; PubMed Scopus Google Scholar, Molday R.S. Biochemistry. 37: PubMed Scopus Google Scholar). Peripherin/Rds and Rom-1 a multisubunit protein complex R.A. Manara S. Collins L. Molday R.S. Kalnins V.I. Neuron. 1992; 8: 1171-1184Abstract Full Text PDF PubMed Scopus (205) Google Scholar, 8.Moritz O.L. Molday R.S. Invest. Ophthalmol. Vis. Sci. 1996; 37: 352-362PubMed Google Scholar, O.L. Molday R.S. Biochemistry. PubMed Scopus Google Scholar). studies that this complex is a composed of peripherin/Rds and Rom-1 Molday R.S. Biochemistry. 1996; PubMed Scopus Google Scholar). disulfide bonds have been generally thought to be in the structure of this complex since a of peripherin/Rds and Rom-1 as disulfide-linked dimers on nonreducing (5.Molday R.S. Hicks D. Molday L.L. Invest. Ophthalmol. Vis. Sci. 1987; 28: 50-61PubMed Google Scholar, 7.Bascom R.A. Manara S. Collins L. Molday R.S. Kalnins V.I. Neuron. 1992; 8: 1171-1184Abstract Full Text PDF PubMed Scopus (205) Google W. A.C. M.M. Bok D. Travis G.H. J. Cell Sci. 1996; PubMed Google Scholar). studies have a cysteine in the large intradiscal loop of peripherin/Rds that is for the of disulfide-linked peripherin/Rds dimers Molday R.S. Biochemistry. 37: PubMed Scopus Google Scholar). the role of intermolecular disulfide bonds in the structure of the have analyzed the oligomeric structure of these proteins from reduced and nonreduced and COS-1 cell membranes by velocity sedimentation, SDS-gel electrophoresis, immunoaffinity and cross-linking. We that peripherin/Rds and Rom-1 associate noncovalently to form a of homomeric and heteromeric core A of core complexes through intermolecular disulfide bonds to form oligomers. These studies to a for the oligomeric structure of peripherin/Rds containing proteins in and the role of these complexes in outer segment morphogenesis and retinal from by as R.S. Molday L.L. J. Cell Biol. 1987; PubMed Scopus (108) Google Scholar). to peripherin/Rds and Rom-1 have been (5.Molday R.S. Hicks D. Molday L.L. Invest. Ophthalmol. Vis. Sci. 1987; 28: 50-61PubMed Google Scholar, 8.Moritz O.L. Molday R.S. Invest. Ophthalmol. Vis. Sci. 1996; 37: 352-362PubMed Google Scholar). with of and a protein of in the in the or absence of by the of or to a of and to an of NEM, The for and the to nonreducing conditions for by as the in peripherin/Rds or Rom-1 as a of by the with a to a in and the a protein of in in the or absence of by the of an of and in containing to a protein of The for to and the for velocity and studies or for of peripherin/Rds and Rom-1. complex from on a immunoaffinity as O.L. Molday R.S. Biochemistry. PubMed Scopus Google Scholar). of with of for in The with of by to protein, and the complex with of containing of the and for COS-1 cell have been Molday R.S. Biochemistry. 37: PubMed Scopus Google Scholar, O.L. Molday R.S. Biochemistry. PubMed Scopus Google Scholar). COS-1 cells with of and as O.L. Molday R.S. Biochemistry. PubMed Scopus Google Scholar). The cells twice with and with of containing and or the cells by the of of and for on The for and the and on protein from or or COS-1 cell membranes or to in and containing in the for for in a the of the and by with for to and The to an of SDS in the absence of reducing and analyzed by and or or complex with and with or for to an of SDS containing for by Peripherin/Rds and Rom-1 as for as membranes with an of SDS in containing and for the in containing and Peripherin/Rds to and Rom-1 to in the protein with SDS containing for The of the proteins confirmed by and the protein by the of and R.S. 1985; PubMed Scopus Google Scholar). Under these the of the peripherin/Rds Rom-1 and Rom-1 of peripherin/Rds as by The of peripherin/Rds and Rom-1 in not be from of since is known to the of peripherin/Rds and to a Rom-1. a result, the peripherin/Rds complex from to as that peripherin/Rds in the the the peripherin/Rds complex from the with The and along with the peripherin/Rds and Rom-1 analyzed by and reducing The of peripherin/Rds and Rom-1 from of the from from as an of or more and with the protein in R.S. 1985; PubMed Scopus Google Scholar). the of disulfide-linked nonreduced in an of consisting of and in The with containing and and the peripherin/Rds and Rom-1 containing complexes to or as protein with SDS in and analyzed nonreducing conditions by and of the in in and with as The complexes with and on as with an of SDS in the absence or of and to an or electrophoresis, the proteins to a and the with the or (5.Molday R.S. Hicks D. Molday L.L. Invest. Ophthalmol. Vis. Sci. 1987; 28: 50-61PubMed Google Scholar, 8.Moritz O.L. Molday R.S. Invest. Ophthalmol. Vis. Sci. 1996; 37: 352-362PubMed Google and for by studies have that a of peripherin/Rds and Rom-1 from as disulfide-linked dimers on nonreducing (5.Molday R.S. Hicks D. Molday L.L. Invest. Ophthalmol. Vis. Sci. 1987; 28: 50-61PubMed Google Scholar, 6.Connell G. Molday R.S. Biochemistry. 1990; 29: 4691-4698Crossref PubMed Scopus (141) Google Scholar, 7.Bascom R.A. Manara S. Collins L. Molday R.S. Kalnins V.I. Neuron. 1992; 8: 1171-1184Abstract Full Text PDF PubMed Scopus (205) Google Scholar, 26.Travis G.L. Sutcliffe J.G. Bok D. Neuron. 1991; 6: 61-70Abstract Full Text PDF PubMed Scopus Google Scholar). the intermolecular disulfide for these dimers be reduced the membrane with for and the of peripherin/Rds on of nonreducing SDS gels. in reduced to by with a of A similar of for peripherin/Rds and for membrane and Rom-1 not In as a reducing in the of to or of this to the intermolecular disulfide on the to a than that for not A to the of intermolecular disulfide bonds to the oligomeric structure of the complex from membranes. In the velocity to oligomeric forms of complexes from nonreduced and reduced membranes. In the from the velocity with to and to nonreducing conditions for the of disulfide-linked dimers by A and the of immunoaffinity complex from reduced membranes. peripherin/Rds and Rom-1 as a with a of a that has been to to a Molday R.S. Biochemistry. 37: PubMed Scopus Google Scholar, Molday R.S. Biochemistry. 1996; PubMed Scopus Google Scholar). by nonreducing conditions that this disulfide-linked Peripherin/Rds containing proteins from nonreduced with to showed a more complex A and peripherin/Rds containing and two Rom-1 containing by velocity the as the reduced complex and this complex consisted of peripherin/Rds and Rom-1 monomers when analyzed on nonreducing SDS gels. a characteristic of a larger This contained both monomers and disulfide-linked dimers of peripherin/Rds and Rom-1 proteins when analyzed on nonreducing SDS gels. Peripherin/Rds containing dimers as a whereas Rom-1 containing dimers a The of the Rom-1 with the peripherin/Rds and to disulfide-linked The of the Rom-1 and to disulfide-linked Rom-1 with as of characteristic of a this Rom-1 and consisted of disulfide-linked peripherin/Rds results when to velocity of the complexes that more the of the of oligomers of not The of peripherin/Rds and Rom-1 in the by velocity by and on the to reducing conditions in which peripherin/Rds and Rom-1 as of peripherin/Rds in the core complex in the oligomer and in the oligomer In the of Rom-1, of Rom-1 in a and in These results indicate that peripherin/Rds and Rom-1 interact through bonds to form core homomeric and heteromeric A of these complexes interact through intermolecular disulfide bonds to form larger a large of which is devoid of Rom-1. peripherin/Rds and Rom-1 expressed in COS-1 cells to a multisubunit complex that as a reducing conditions Molday R.S. Biochemistry. 37: PubMed Scopus Google Scholar, O.L. Molday R.S. Biochemistry. PubMed Scopus Google Scholar, Molday R.S. Biochemistry. 1996; PubMed Scopus Google Scholar). We have the to for the disulfide-linked of individually expressed peripherin/Rds and Rom-1. in A both peripherin/Rds and Rom-1 from membranes as a as O.L. Molday R.S. Biochemistry. PubMed Scopus Google Scholar). by nonreducing conditions that these complexes disulfide-linked The velocity of peripherin/Rds from nonreduced COS-1 cell membranes showed larger peripherin/Rds oligomers in to the core complex The oligomers consisted of disulfide-linked peripherin/Rds dimers when analyzed by nonreducing In Rom-1 from nonreduced COS-1 cell membranes showed little tendency to form disulfide-linked as the core complex intermolecular disulfide bonds 150 in the large intradiscal loop of peripherin/Rds has been to be for disulfide-linked of peripherin/Rds Molday R.S. Biochemistry. 37: PubMed Scopus Google Scholar). the role of this cysteine in the and disulfide-linked of the peripherin/Rds in the from reduced and nonreduced COS-1 cell membranes as a core complex devoid of intermolecular disulfide bonds. These studies indicate that Cys-150 disulfide-linked of peripherin/Rds core complexes. to and disulfide-linked of peripherin/Rds and Rom-1. In these and nonreduced membranes in on a and with for by reducing The in that a of peripherin/Rds from reduced membranes to a to a when a In of peripherin/Rds from membranes a of molecular in to monomers and dimers A similar pattern of when for Rom-1 not These results indicate that peripherin/Rds and Rom-1 from reduced membranes whereas the protein from nonreduced membranes larger a that is with the of large oligomers in velocity the of disulfide-linked and an immunoaffinity to linked SDS complexes from nonreduced membranes to the of disulfide-linked and from reduced membranes to the of The in SDS to with to the SDS and to to peripherin/Rds and Rom-1 containing for by and the of this reduced membranes with SDS and peripherin/Rds and Rom-1 on a or by in peripherin/Rds only in the and Rom-1 in the of Rom-1 only in the of and peripherin/Rds in the The of disulfide-linked dimers nonreduced membranes. of the and from and The of contained Rom-1 and a of disulfide-linked Rom-1 devoid of The contained both peripherin/Rds and disulfide-linked This more than the Rom-1 disulfide-linked in the a of disulfide-linked peripherin/Rds and that are not in this gel Rom-1 containing the in the The of this is not known the The from the contained peripherin/Rds and disulfide-linked Rom-1. The to Rom-1 and a disulfide-linked peripherin/Rds also in the this to contain These results indicate that oligomers are through disulfide and of the core complexes. The of dimers of peripherin/Rds and Rom-1 from also in the of the contained Rom-1 The contained both peripherin/Rds and Rom-1 also in the that a of this is composed of the core complexes peripherin/Rds be to or to Rom-1 to however, is in two Rom-1 The of peripherin/Rds and Rom-1 in by the of protein in the and of a Peripherin/Rds only in the and of the protein by Rom-1 in both the and and of the of Rom-1 in the This Rom-1 peripherin/Rds as monomers by nonreducing The of Rom-1 to form disulfide-linked in the absence of peripherin/Rds is with the of Rom-1 expressed in COS-1 The complex of disc membranes thought to of disulfide-linked of peripherin/Rds and Rom-1 that interact noncovalently to form a protein R.A. Manara S. Collins L. Molday R.S. Kalnins V.I. Neuron. 1992; 8: 1171-1184Abstract Full Text PDF PubMed Scopus (205) Google Scholar, Molday R.S. Biochemistry. 1996; PubMed Scopus Google Scholar). This on the that a of peripherin/Rds and Rom-1 as disulfide-linked on nonreducing SDS Rom-1 with peripherin/Rds by immunoaffinity and complex with a the in the of and the of disulfide-linked dimers these conditions not indicate that this is not results a as in Peripherin/Rds and Rom-1 in membranes interact noncovalently to form multisubunit core complexes. A of the complexes intermolecular disulfide bonds to form and oligomers. The core complex is a of homomeric and heteromeric multisubunit proteins homomeric and heteromeric core proteins are the and form disulfide-linked oligomers. Rom-1 homomeric core protein only of these complexes and little to form disulfide-linked oligomers. The size of the core complex has been to be a by Molday R.S. Biochemistry. 1996; PubMed Scopus Google Scholar). of the however, dimers by and studies indicate that the large loop is in interactions Molday R.S. Proc. Natl. Acad. Sci. U. S. A. 1996; PubMed Scopus Google Scholar, Molday R.S. Biochemistry. 37: PubMed Scopus Google Scholar). is that in this segment are not for of the may an of the size of the to the of studies are to the size of the core of oligomers are by velocity nonreducing One as is in size and both peripherin/Rds and Rom-1 of the in the in intermolecular disulfide bonds since both monomers and dimers are by nonreducing The size of this oligomer is to be twice the size of the core complex on the of the to molecular R.G. J. Biol. Full Text PDF PubMed Google and the that both similar of core The intermolecular disulfide bonds that the peripherin/Rds containing core complexes are formed two peripherin/Rds peripherin/Rds and Rom-1 and two Rom-1 The of oligomers is composed of peripherin/Rds of which in intermolecular disulfide bonds. The oligomeric are in of membranes with results in the of the oligomers core complexes that the intermolecular disulfide bonds are to this reducing and essential for that peripherin/Rds is twice the of Rom-1 in a that is with the of a of peripherin/Rds by velocity studies to the of peripherin/Rds and Rom-1 core complexes in R.A. Manara S. Collins L. Molday R.S. Kalnins V.I. Neuron. 1992; 8: 1171-1184Abstract Full Text PDF PubMed Scopus (205) Google O.L. Molday R.S. Invest. Ophthalmol. Vis. Sci. 1996; 37: 352-362PubMed Google Scholar). This may be to the to of peripherin/Rds and Rom-1 in the of large of by the of in these Peripherin/Rds and Rom-1 expressed in COS-1 cells a similar pattern of as in A of peripherin/Rds core complex through intermolecular disulfide bonds to form and oligomers of in the of the in these oligomers in intermolecular disulfide Rom-1 expressed in COS-1 cells also a core this protein little tendency to form disulfide-linked as in studies have confirmed that disulfide-linked of peripherin/Rds is by Cys-150 the large intradiscal loop of the The in Rom-1 is also to in intermolecular disulfide heteromeric core complexes. in the absence of two residues of Rom-1 little tendency to form intermolecular disulfide to or of these These studies indicate that peripherin/Rds a tendency to form disulfide-linked oligomers of The of peripherin/Rds with Rom-1 in the core complex the size of the oligomers and the of that in intermolecular disulfide Rom-1 be as a of peripherin/Rds disulfide bonds are known to be in the of multisubunit proteins and oligomeric complexes. The and of and the and of the are by disulfide bonds. disulfide is in and of P.A. J. PubMed Google stabilization of G. J. Cell Biol. PubMed Scopus Google and of an protein in and J.E. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). We that the of peripherin/Rds plays an role in outer segment disc morphogenesis and This is on the The cysteine residues for intermolecular disulfide bonds in peripherin/Rds and in are conserved in peripherin/Rds and Rom-1 proteins analyzed to date Molday R.S. Biochemistry. 37: PubMed Scopus Google Scholar). of peripherin/Rds is a of these proteins (5.Molday R.S. Hicks D. Molday L.L. Invest. Ophthalmol. Vis. Sci. 1987; 28: 50-61PubMed Google Scholar, 7.Bascom R.A. Manara S. Collins L. Molday R.S. Kalnins V.I. Neuron. 1992; 8: 1171-1184Abstract Full Text PDF PubMed Scopus (205) Google Scholar, 13.Connell G. Bascom R.A. Molday L.L. Reid D. McInnes R.R. Molday R.S. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 723-726Crossref PubMed Scopus (237) Google Scholar, 26.Travis G.L. Sutcliffe J.G. Bok D. Neuron. 1991; 6: 61-70Abstract Full Text PDF PubMed Scopus Google Scholar, W. A.C. M.M. Bok D. Travis G.H. J. Cell Sci. 1996; PubMed Google Scholar). have been to disc Invest. Vis. Sci. 1994; and a protein that in the and of disulfide is in and R. Molday, In peripherin/Rds and Rom-1 containing homomeric and heteromeric core complexes are to in the membrane of and in to the of outer proteins may disulfide-linked from this the of the outer segment, of peripherin/Rds containing homomeric and heteromeric core complexes disc membranes to the rim region as of outer segment The that membrane proteins membrane is not The structural protein, of is a The of these complexes on membranes interact with to membrane L. P. Neuron. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). In this case, however, through mechanism disulfide-linked of peripherin/Rds containing core complexes a membrane. These oligomers be to the disc rim or interactions with outer segment proteins that in outer segment are to more the role of of peripherin/Rds in disc Peripherin/Rds and Rom-1 with to role in outer segment Peripherin/Rds is essential for outer segment morphogenesis since homozygous rds mice this protein fail to form outer segments (10.Sanyal S. Jansen H.G. Neurosci. Lett. 1981; 21: 23-26Crossref PubMed Scopus (166) Google Scholar). Rom-1, on the to the structure of the outer segment discs since homozygous rom-1 mice outer segments with slightly discs (22.Clarke, G., Goldberg, A. F. X., Vidgen, D., Collins, L., Ploder, L., Schwarz, L., Molday, L. L., Rossant, J., Szél, A., Molday, R. S., Birch, D. G., and McInnes, R. R. (2000) Nat. Genet., in pressGoogle Scholar). the dominant role of peripherin/Rds in outer segment disc In to more than Rom-1 in peripherin/Rds is required for the of and disulfide-linked a that may be crucial for disc morphogenesis as Rom-1, on the not form and not be to be essential for disc Rom-1 may to the of peripherin/Rds oligomer through interactions with peripherin/Rds and the size of the discs outer segment A large of mutations in the large intradiscal loop of peripherin/Rds have been linked to a variety of human retinal degenerative diseases. studies have that of these mutations protein and Molday R.S. Proc. Natl. Acad. Sci. U. S. A. 1996; PubMed Scopus Google Scholar, Molday R.S. Biochemistry. 37: PubMed Scopus Google Scholar). A of the of this large loop may be the of the peripherin/Rds to form intermolecular disulfide bonds required for mutations in Rom-1 have since disulfide-linked of Rom-1 is not crucial to outer segment morphogenesis and structure. In have that peripherin/Rds and Rom-1 associate noncovalently to form homomeric and heteromeric core complexes. Peripherin/Rds containing complexes interact intermolecular disulfide bonds to form oligomers that may play an role in rod and cone outer segment We for the and for the of this

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