The Effect of Lipid Environment and Retinoids on the ATPase Activity of ABCR, the Photoreceptor ABC Transporter Responsible for Stargardt Macular Dystrophy

ABCR is a photoreceptor-specific ATP-binding cassette transporter that has been linked to various retinal diseases, including Stargardt macular dystrophy, and implicated in retinal transport across rod outer segment (ROS) membranes. We have examined the ATPase and GTPase activity of detergent-solubilized and reconstituted ABCR. 3-[(3-Cholamidopropyl)dimethylammonio]-1-propanesulfonic acid-solubilized ABCR had ATPase and GTPase activity (K m ∼75 μm;V max ∼ 200 nmol/min/mg) that was stimulated 1.5–2-fold by all-trans-retinal and dependent on phospholipid and dithiothreitol. The K m for ATP decreased to ∼25 μm after reconstitution, whereas theV max was strongly dependent on the lipid used for reconstitution. ABCR reconstituted in ROS phospholipid had aV max for basal and retinal activated ATPase activity that was 4–6 times higher than for ABCR in soybean or brain phospholipid. This enhanced activity was mainly due to the high phosphatidylethanolamine (PE) content of ROS membranes. PE was also required for retinoid-stimulated ATPase activity. ATPase activity of ABCR was stimulated by the addition ofN-retinylidene-PE but not the reduced derivative, retinyl-PE. ABCR expressed in COS-1 cells also exhibited retinal-stimulated ATPase activity similar to that of the native protein. These results support the view that ABCR is an active retinoid transporter, the nucleotidase activity of which is strongly influenced by its lipid environment. ABCR is a photoreceptor-specific ATP-binding cassette transporter that has been linked to various retinal diseases, including Stargardt macular dystrophy, and implicated in retinal transport across rod outer segment (ROS) membranes. We have examined the ATPase and GTPase activity of detergent-solubilized and reconstituted ABCR. 3-[(3-Cholamidopropyl)dimethylammonio]-1-propanesulfonic acid-solubilized ABCR had ATPase and GTPase activity (K m ∼75 μm;V max ∼ 200 nmol/min/mg) that was stimulated 1.5–2-fold by all-trans-retinal and dependent on phospholipid and dithiothreitol. The K m for ATP decreased to ∼25 μm after reconstitution, whereas theV max was strongly dependent on the lipid used for reconstitution. ABCR reconstituted in ROS phospholipid had aV max for basal and retinal activated ATPase activity that was 4–6 times higher than for ABCR in soybean or brain phospholipid. This enhanced activity was mainly due to the high phosphatidylethanolamine (PE) content of ROS membranes. PE was also required for retinoid-stimulated ATPase activity. ATPase activity of ABCR was stimulated by the addition ofN-retinylidene-PE but not the reduced derivative, retinyl-PE. ABCR expressed in COS-1 cells also exhibited retinal-stimulated ATPase activity similar to that of the native protein. These results support the view that ABCR is an active retinoid transporter, the nucleotidase activity of which is strongly influenced by its lipid environment. phosphatidylethanolamine rod outer segment 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid dioleoylphosphatidylethanolamine dioleoylphosphatidylcholine 1-stearoyl-2-docosahexaenoylphosphatidylcholine 1-stearoyl-2-docosahexaenoylphosphatidylethanolamine dithiothreitol phosphatidylcholine phosphate-buffered saline high pressure liquid chromatography ABCR, also known as the rim protein, is an abundant high molecular weight membrane glycoprotein found in photoreceptor outer segment disc membranes (1.Papermaster D.S. Schneider B.G. Zorn M.A. Kraehenbuhl J.P. J. Cell Biol. 1978; 78: 415-425Crossref PubMed Scopus (182) Google Scholar, 2.Illing M. Molday L.L. Molday R.S. J. Biol. Chem. 1997; 272: 10303-10310Abstract Full Text Full Text PDF PubMed Scopus (251) Google Scholar, 3.Sun H. Nathans J. Nat. Genet. 1997; 17: 15-16Crossref PubMed Scopus (213) Google Scholar). Primary structural analysis indicates that ABCR is a member of the superfamily of ATP-binding cassette proteins that typically function in the active transport of various substances across cell membranes (2.Illing M. Molday L.L. Molday R.S. J. Biol. Chem. 1997; 272: 10303-10310Abstract Full Text Full Text PDF PubMed Scopus (251) Google Scholar, 4.Allikmets R. Singh N. Sun H. Shroyer N.F. Hutchinson A. Chidambaram A. Gerrard B. Baird L. Stauffer D. Peiffer A. Rattner A. Smallwood P. Li Y. Anderson K.L. Lewis R.A. Nathans J. Leppert M. Dean M. Lupski J.R. Nat. Genet. 1997; 15: 236-246Crossref PubMed Scopus (1122) Google Scholar, 5.Azarian S.M. Travis G.H. FEBS Lett. 1997; 409: 247-252Crossref PubMed Scopus (152) Google Scholar). Like other eukaryotic ABC transporters, such as P-glycoprotein and cystic fibrosis transmembrane conductance regulator, ABCR is organized in two homologous, tandem-arranged halves, each containing a cytoplasmic nucleotide binding domain preceded by a hydrophobic domain consisting of multiple membrane spanning segments. The gene encoding ABCR has been implicated in a variety of retinal degenerative diseases associated with a loss in vision. Over 80 different mutations in ABCR have been found in patients with Stargardt macular dystrophy, a juvenile onset, autosomal recessive disease characterized by decreased visual acuity, bilateral atrophy of the central (macula) retina, accumulation of fluorescent yellow deposits in the retinal pigment epithelium, and delayed dark adaptation (4.Allikmets R. Singh N. Sun H. Shroyer N.F. Hutchinson A. Chidambaram A. Gerrard B. Baird L. Stauffer D. Peiffer A. Rattner A. Smallwood P. Li Y. Anderson K.L. Lewis R.A. Nathans J. Leppert M. Dean M. Lupski J.R. Nat. Genet. 1997; 15: 236-246Crossref PubMed Scopus (1122) Google Scholar, 6.Nasonkin I. Illing M. Koehler M.R. Schmid M. Molday R.S. Weber B.H.F. Hum. Genet. 1998; 102: 21-26Crossref PubMed Scopus (79) Google Scholar, 7.Fishman G.A. Stone E.M. Grover S. Derlacki D.J. Haines H.L. Hockey R.R. Arch. Ophthalmol. 1999; 117: 504-510Crossref PubMed Scopus (186) Google Scholar, 8.Lewis R.A. Shroyer N.F. Singh N. Allikmets R. Hutchinson A. Li Y. Lupski J.R. Leppert M. Dean M. Am. J. Hum. Genet. 1999; 64: 422-434Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar). Mutations in ABCR have also been linked to individuals with fundus flavimaculatus, a late-onset variant of Stargardt macular dystrophy (9.Souied E.H. Ducroq D. Rozet J.M. Gerber S. Perrault I. Sterkers M. Benhamou N. Munnich A. Coscas G. Soubrane G. Kaplan J. Invest. Ophthalmol. Vis. Sci. 1999; 40: 2740-2744PubMed Google Scholar), autosomal recessive retinitis pigmentosa (10.Martinez-Mir A. Paloma E. Allikmets R. Ayuso C. del Rio T. Dean M. Vilageliu L. Gonzalez-Duarte R. Balcells S. Nat. Genet. 1998; 18: 11-12Crossref PubMed Scopus (333) Google Scholar), cone-rod dystrophy (11.Cremers F.P. van de Pol D.J. van Driel M. den Hollander A.I. van Haren F.J. Knoers N.V. Tijmes N. Bergen A.A. Rohrschneider K. Blankenagel A. Pinckers A.J. Deutman A.F. Hoyng C.B. Hum. Mol. Genet. 1998; 7: 355-362Crossref PubMed Scopus (465) Google Scholar), and age-related macular dystrophy (12.Allikmets R. Shroyer N.F. Singh N. Seddon J.M. Lewis R.A. Bernstein P.S. Peiffer A. Zabriskie N.A. Li Y. Hutchinson A. Dean M. Lupski J.R. Leppert M. Science. 1997; 277: 1805-1807Crossref PubMed Scopus (757) Google Scholar, 13.Souied E.H. Ducroq D. Gerber S. Ghazi I. Rozet J.M. Perrault I. Munnich A. Dufier J.L. Coscas G. Soubrane G. Kaplan J. Am. J. Ophthalmol. 1999; 128: 173-178Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar). The substrate(s) transported by ABCR is not yet known. However, localization of ABCR to photoreceptor outer segment disc membranes led to the initial suggestion that ABCR may function to transport retinoids across the disc membrane (2.Illing M. Molday L.L. Molday R.S. J. Biol. Chem. 1997; 272: 10303-10310Abstract Full Text Full Text PDF PubMed Scopus (251) Google Scholar, 3.Sun H. Nathans J. Nat. Genet. 1997; 17: 15-16Crossref PubMed Scopus (213) Google Scholar, 4.Allikmets R. Singh N. Sun H. Shroyer N.F. Hutchinson A. Chidambaram A. Gerrard B. Baird L. Stauffer D. Peiffer A. Rattner A. Smallwood P. Li Y. Anderson K.L. Lewis R.A. Nathans J. Leppert M. Dean M. Lupski J.R. Nat. Genet. 1997; 15: 236-246Crossref PubMed Scopus (1122) Google Scholar). The putative role of ABCR as a retinal transporter is supported by two recent studies. In one study, purified ABCR reconstituted into brain lipid vesicles displayed ATPase activity that was stimulated up to 5-fold by retinal (14.Sun H. Molday R.S. Nathans J. J. Biol. Chem. 1999; 274: 8269-8281Abstract Full Text Full Text PDF PubMed Scopus (311) Google Scholar). Substrates that are actively transported across cell membranes by P-glycoprotein, histidine permease, multidrug resistance-associated protein, and the canalicular multispecific organic anion transporter (cMOAT/multidrug resistance-associated protein 2) also activate the ATPase activity of these proteins (15.Ambudkar S.V. Lelong I.H. Zhang J. Cardarelli C.O. Gottesman M.M. Pastan I. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 8472-8476Crossref PubMed Scopus (382) Google Scholar, 16.Sarkadi B. Price E.M. Boucher R.C. Germann U.A. Scarborough G.A. J. Biol. Chem. 1992; 267: 4854-4858Abstract Full Text PDF PubMed Google Scholar, 17.Shapiro A.B. Ling V. J. Biol. Chem. 1994; 269: 3745-3754Abstract Full Text PDF PubMed Google Scholar, 18.Sharom F.J., Yu, X. Chu J.W.K. Doige C.A. Biochem. J. 1995; 308: 381-390Crossref PubMed Scopus (200) Google Scholar, 19.Urbatsch I.L. Senior A.E. Arch. Biochem. Biophys. 1995; 316: 135-140Crossref PubMed Scopus (132) Google Scholar, 20.Hagmann W. Nies A.T. J. M. H. D. J. Biochem. 1999; PubMed Scopus Google Scholar, J.R. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). In a study, an has been that delayed dark a in all-trans-retinal and and an accumulation of the in and retinal pigment cells J. S.M. Travis G.H. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). of these are in individuals with Stargardt disease and are with an accumulation of in photoreceptor membranes due to transport of retinoid across disc membranes. of an to the structural and of ABCR, have the of various and retinoid on the nucleotidase activity of ABCR ROS membranes. that detergent-solubilized and reconstituted ABCR ATPase and GTPase activity that is strongly influenced by the lipid and the of retinoid We also that ABCR expressed in COS-1 cells retinal-stimulated ATPase activity to that of the native protein. reduced soybean and and was a of The and brain lipid The of was as m soybean m m m and in and in or in and in of and R. D. Scopus Google Scholar). the of retinal and was by the of Anderson and PubMed Scopus Google Scholar). was with of in of a consisting of and by The was and to for the of the a of was the initial The purified by on a by a C.A. M. K. J. J. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar). The a of in to a of by with also a of the as the with an of of the by addition of the to with PubMed Scopus Google Scholar). The of was The of was by ROS membranes on a as R.S. Molday L.L. J. Cell Biol. PubMed Scopus Google and in ROS membranes by the of M. G.H. J. Biol. Chem. Full Text PDF Google Scholar), with to the of retinal with and to the of the that are abundant in ROS Biophys. PubMed Scopus (132) Google Scholar, S. Biophys. PubMed Scopus Google Scholar). ROS membranes times in and in of the of of to and of was to the and the was on for retinal to the The was with of and of containing as an The organic was the and with of m and of The organic was and the in of by and to a chromatography a The was in a with consisting of by The retinal the whereas the the The with a and the by containing The of phospholipid was by lipid the of and X. G. J. 1992; Full Text PDF PubMed Google Scholar). The was used to the ABCR protein ROS membranes as (2.Illing M. Molday L.L. Molday R.S. J. Biol. Chem. 1997; 272: 10303-10310Abstract Full Text Full Text PDF PubMed Scopus (251) Google Scholar, H. Molday R.S. Nathans J. J. Biol. Chem. 1999; 274: 8269-8281Abstract Full Text Full Text PDF PubMed Scopus (311) Google Scholar). in the dark or ROS membranes of in and for in a two in the membrane was to of containing and for The was as and the was for with of in C. The to a μm and with of ABCR was by the for in of containing The was and the with an of to a of of ABCR was reconstituted into soybean phospholipid vesicles by of purified ABCR and soybean lipid in B. for the was for and of ABCR was reconstituted into brain and ROS the of Sun (14.Sun H. Molday R.S. Nathans J. J. Biol. Chem. 1999; 274: 8269-8281Abstract Full Text Full Text PDF PubMed Scopus (311) Google Scholar). of brain lipid other or ROS phospholipid ∼ other with of in ABCR was and the was on for was and the vesicles of in a μm that had been in E. The containing reconstituted ABCR was by pressure with a and was to ATPase activity. The of in a was by chromatography as C. M. W. E. M. D. J.M. K. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of ABCR in or reconstituted into and other The was with the addition of of a ATP the ATP was for ABCR and μm for reconstituted ABCR. of and the was of the was a and in m The was to a for and in a to ATP and The of the of to the initial of ATP in the was was in to ATP which was the GTPase activity was in an The protein of ROS membrane was by the The of protein in was by the of with that of after content of reconstituted ABCR was by analysis known of purified ABCR protein. and with an and used to protein by on and to membranes for in a a consisting of The membrane was in containing for and with in for and with in for by enhanced the ABCR (4.Allikmets R. Singh N. Sun H. Shroyer N.F. Hutchinson A. Chidambaram A. Gerrard B. Baird L. Stauffer D. Peiffer A. Rattner A. Smallwood P. Li Y. Anderson K.L. Lewis R.A. Nathans J. Leppert M. Dean M. Lupski J.R. Nat. Genet. 1997; 15: 236-246Crossref PubMed Scopus (1122) Google Scholar, 6.Nasonkin I. Illing M. Koehler M.R. Schmid M. Molday R.S. Weber B.H.F. Hum. Genet. 1998; 102: 21-26Crossref PubMed Scopus (79) Google was into the and of COS-1 cells in with and and a with of and of for cells in and by in The cells for and the was in of containing and ABCR was purified on a as for ABCR ROS that the was of cells used for of The ATPase activity of ABCR ROS membranes was various the and activity in the of soybean and ABCR exhibited a basal ATPase activity that was stimulated up to by and all-trans-retinal reduced and and had on the basal ATPase activity of ABCR. The activity of ABCR was dependent on the of and Over of the basal ATPase activity was or soybean phospholipid was and activity also the ATPase activity of the nucleotide activity of ABCR. the ATPase activity of purified ABCR was as a function of the all-trans-retinal or the of the of GTPase activity by all-trans-retinal in a activity In of ATPase activity was with The ATPase activity of ABCR was ATPase by all-trans-retinal was ABCR was of ABCR for in the loss of of the ATPase activity of ABCR. of ATP of the basal ATPase activity the was in the of ABCR exhibited ATPase and GTPase in the basal ATPase and GTPase activated by all-trans-retinal with μm The ATPase and GTPase Sun (14.Sun H. Molday R.S. Nathans J. J. Biol. Chem. 1999; 274: 8269-8281Abstract Full Text Full Text PDF PubMed Scopus (311) Google that ABCR reconstituted into brain lipid and brain PE basal and retinal-stimulated ATPase activity. We have reconstituted purified ABCR into various phospholipid in to the of the lipid on the basal and retinal-stimulated ATPase activity of ABCR. the of ATP on ATP for ABCR reconstituted into ROS phospholipid The K m and for ATP by detergent-solubilized and reconstituted ABCR are in I. m for basal ATPase activity of ABCR reconstituted in and ROS phospholipid are similar (K m ∼ μm but than for ABCR (K m ∼ μm The lipid had a on the max of the reconstituted The max of ABCR reconstituted into ROS phospholipid max nmol/min/mg) is times higher than ABCR reconstituted into soybean phospholipid and times higher than ABCR in brain lipid but to that for the protein theV max and K m for ATP by ABCR reconstituted into each of retinal was in retinal the max by for ABCR in ROS and brain but 1.5–2-fold for ABCR in soybean of ATPase activity of purified ABCR reconstituted in different lipid m for outer activity was or after in brain or rod outer segment K m and max the of ATP ATP in the or of μm are the of with with a in in a ATPase activity was or after in brain or rod outer segment K m and max the of ATP ATP in the or of μm are the of with with a in In addition to the of ATP the lipid also influenced the of ABCR. ABCR, the basal and retinal-stimulated activity of reconstituted ABCR was by for The of all-trans-retinal and on the ATPase activity of ABCR in ROS and brain was also that ATPase a μm high retinal an of ATPase activity was typically for ABCR reconstituted in ROS also stimulated the ATPase activity of ABCR reconstituted in brain and ROS but was and higher ROS membranes are known to a high content of PE and acid containing PubMed Scopus Google Scholar, S. Biophys. PubMed Scopus Google Scholar). these are for the ATPase activity of ABCR in ROS the basal and retinal-stimulated ATPase activity of ABCR reconstituted into brain lipid vesicles containing or in of the brain lipid with or in a in basal and retinal-stimulated ATPase with the In the addition of or to brain lipid in a in basal and retinal-stimulated ATPase activity. has been known that retinal with PE to the PubMed Scopus Google Scholar, D.J. Biochem. J. PubMed Scopus Google Scholar). the to which retinal with PE in lipid used for reconstitution, was to brain lipid vesicles a the was by the addition of and the retinoids and by and the and of these PubMed Scopus Google D.J. Biochem. J. PubMed Scopus Google Scholar). of the all-trans-retinal to the vesicles with PE to that retinal a with PE in was of to have on the ATPase activity of ABCR. in the addition of to ABCR reconstituted in brain lipid in of the ATPase activity by The addition of μm of in a in ATPase activity of J. T. and R. S. was of ATPase activity by μm or PE ABCR was reconstituted in or vesicles of retinoids on the ATPase activity of ABCR reconstituted in ABCR reconstituted in brain or was for ATPase activity in the of μm μm or μm The retinal and PE is known to was to brain lipid vesicles or into its an initial of μm was with vesicles for up to analysis that of was as the whereas the was as the the retinal-stimulated ATPase activity in purified ABCR is a of ABCR than a ATPase of ROS ABCR was expressed in COS-1 and the ATPase activity of the protein was in the and of a and a of ABCR purified COS-1 in the of ABCR ROS the expressed and purified ABCR on as a protein with an molecular of Over of ABCR expressed in COS-1 cells to the into brain phospholipid ABCR basal and retinal-stimulated ATPase activity similar to that of the native protein activity of ABCR purified COS-1 ABCR was and purified COS-1 cells and reconstituted in brain lipid COS-1 cells was also to ATPase activity. ATP was in the or of The of ATP a by and reconstituted protein cells is In study, have examined the of and other on the nucleotidase activity of ABCR purified ROS disc membranes. and a are required ATPase activity is detergent-solubilized ABCR is purified in the of phospholipid or a also that the ATP is to as as of one or of ABCR. These are with P-glycoprotein, an ABC transporter that with ABCR, the nucleotide binding A.B. Ling V. J. Biol. Chem. 1994; 269: 3745-3754Abstract Full Text PDF PubMed Google Scholar, 18.Sharom F.J., Yu, X. Chu J.W.K. Doige C.A. Biochem. J. 1995; 308: 381-390Crossref PubMed Scopus (200) Google Scholar, 19.Urbatsch I.L. Senior A.E. Arch. Biochem. Biophys. 1995; 316: 135-140Crossref PubMed Scopus (132) Google Scholar, Senior A.E. J. Biol. Chem. Full Text PDF PubMed Google Scholar). In the of soybean ABCR basal ATPase activity that is stimulated up to by and This on ABCR is for retinal and a of the retinoid had on the basal activity of ABCR. These with of (14.Sun H. Molday R.S. Nathans J. J. Biol. Chem. 1999; 274: 8269-8281Abstract Full Text Full Text PDF PubMed Scopus (311) Google Scholar), that the linked to PE a and the retinoid are required for ATPase Sun (14.Sun H. Molday R.S. Nathans J. J. Biol. Chem. 1999; 274: 8269-8281Abstract Full Text Full Text PDF PubMed Scopus (311) Google that the ATPase activity of ABCR in a of brain PE and was not stimulated by retinal to reconstitution. The activity of ATP in the was The the and the one (14.Sun H. Molday R.S. Nathans J. J. Biol. Chem. 1999; 274: 8269-8281Abstract Full Text Full Text PDF PubMed Scopus (311) Google may due to the different lipid used of ABCR, the of protein or the of retinal-stimulated ATPase activity of ABCR. The lipid the of ATP by ABCR. in the K m for basal ATPase of ABCR into lipid of the of a lipid may the of the ATP and ABCR. The lipid also the max for ATP The max for ABCR reconstituted into soybean or brain phospholipid vesicles are than for detergent-solubilized ABCR The soybean and brain phospholipid may in ABCR to ATP in a in theV max of ABCR reconstituted into ROS disc is higher than the max of ABCR reconstituted into brain or soybean and to the basal activity of purified P-glycoprotein, cystic fibrosis transmembrane conductance regulator, and multidrug resistance-associated protein A.B. Ling V. J. Biol. Chem. 1994; 269: 3745-3754Abstract Full Text PDF PubMed Google J.R. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar, C. M. W. E. M. D. J.M. K. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). We the that the high of PE of disc lipid is acid of ROS may a for ABCR. This was by the of and on the ATPase activity of ABCR reconstituted in brain and the ATPase activity of ABCR in brain whereas and decreased the that a high PE content the basal and retinal-stimulated ATPase activity of ABCR. The in activity with in by the of brain lipid PE by The of PE in retinal activated ATPase activity of ABCR is by the that ABCR reconstituted in lipid vesicles is of retinoid This indicates that the of retinoid binding the membrane domain of ABCR to the ATPase activity of the nucleotide binding of ABCR a lipid in The lipid is known to the ATPase and binding of P-glycoprotein F.J., Yu, X. Chu J.W.K. Doige C.A. Biochem. J. 1995; 308: 381-390Crossref PubMed Scopus (200) Google I.L. Senior A.E. Arch. Biochem. Biophys. 1995; 316: 135-140Crossref PubMed Scopus (132) Google Scholar, Y. F.J. 1999; PubMed Scopus Google Scholar). In the phospholipid is and P-glycoprotein ATPase whereas PE and J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google have also that the nucleotide binding of P-glycoprotein with the transmembrane PE content is known to the lipid A.B. Ling V. J. Biol. Chem. 1994; 269: 3745-3754Abstract Full Text PDF PubMed Google Scholar). The of ABCR for ATP in such membrane may also to the basal ATPase activity in containing a high PE have that all-trans-retinal with PE in disc membranes to the PubMed Scopus Google PubMed Scopus Google Scholar). This the that retinal is for of ATPase activity of ABCR. In an to the of on the ATPase activity of reconstituted ABCR. in of ATP However, analysis the addition of retinal to brain lipid membranes that an is retinal the of the for ATPase of ABCR. We have to by the reduced the ATPase activity of ABCR. This to the ATPase activity of ABCR. The of the retinoid for ATPase of ABCR was also by the of retinal and on the ATPase activity of ABCR reconstituted into However, retinoid stimulated ATP by ABCR in lipid environment. to the retinal for ATPase of ABCR, that such membranes containing of This strongly that PE is required to the binding of retinoids the transmembrane domain of ABCR to the ATPase activity of the nucleotide binding support the view that ABCR may function to retinal to by the to the cytoplasmic of the disc membrane or retinal the disc that activate the ATPase activity of P-glycoprotein and other ABC are also for transport by these of the ATPase activity of ABCR by retinal that these may also actively transported across disc membranes by ABCR. with Stargardt mutations in ABCR are known to delayed dark adaptation and in the of C.A. M. K. J. J. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar, C. 1995; 15: PubMed Scopus Google Scholar, M. van de 1997; PubMed Scopus Google Scholar, M.R. PubMed Scopus Google Scholar, N. J. K. J. Am. Chem. Scopus (186) Google Scholar). These on the of a of and accumulation of in disc membranes. recent also reduced dark adaptation of and accumulation of to J. S.M. Travis G.H. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). are to the for ABCR and the of transport across disc membranes. rod similar of ATP and was of to ABCR as as ATP that the of ATP and by purified ABCR are basal GTPase activity is stimulated by similar of These results are with that ABCR ATP and (2.Illing M. Molday L.L. Molday R.S. J. Biol. Chem. 1997; 272: 10303-10310Abstract Full Text Full Text PDF PubMed Scopus (251) Google Scholar). is a for P-glycoprotein F.J., Yu, X. Chu J.W.K. Doige C.A. Biochem. J. 1995; 308: 381-390Crossref PubMed Scopus (200) Google Scholar, Senior A.E. J. Biol. Chem. Full Text PDF PubMed Google and not support transport by the transporter, T. B. B. J. L. J. A.F. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). to is to support the active transport function of ABCR. have that ABCR expressed in COS-1 The purified and reconstituted protein basal and retinal-stimulated ATPase activity similar to ABCR native ROS membranes. This that the ATPase activity in ABCR ROS is due to ABCR and not a ATPase This cell in the analysis of ABCR and mutations in ABCR Stargardt disease and We and Nathans for and the ABCR used in and for with

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