RPE65 Is Not an 11-cis-specific Isomerase
18. Redmond, T. M., Gentleman, S., Duncan, T., Yu, S., Wiggert, B., Gantt, E.,
and Cunningham, F. X., Jr. (2001) J. Biol. Chem. 276, 6560–6565
19. Kiefer, C., Hessel, S., Lampert, J. M., Vogt, K., Lederer, M. O., Breithaupt,
D. E., and von Lintig, J. (2001) J. Biol. Chem. 276, 14110–14116
20. von Lintig, J., and Vogt, K. (2000) J. Biol. Chem. 275, 11915–11920
21. Oberhauser, V., Voolstra, O., Bangert, A., von Lintig, J., and Vogt, K.
(2008) Proc. Natl. Acad. Sci. U.S.A. 105, 19000–19005
ity is not known and will require a crystal structure for precise
clarification.
In conclusion, RPE65 may harness the ability of retinoids to
form carbocations (55) or radical cations (56) to produce cis iso-
mers of retinol. Although RPE65 can generate both 11-cis- and
13-cis-retinol, the innate selectivity of the visual cycle for 11-cis
retinoids (35) ensures that only 11-cis-retinol is made under nor-
mal physiological conditions. As in aberrant physiological states
(28), a relaxation in isomer selectivity allows 13-cis-retinol forma-
tion to occur. Taken together, our findings specify that: 1) retinoid
isomerization in the visual cycle occurs by a carbocation/radical
cation mechanism and 2) 11-cis selectivity ultimately depends on
visual cycle proteins downstream of RPE65.
22. Kloer, D. P., Ruch, S., Al-Babili, S., Beyer, P., and Schulz, G. E. (2005)
Science 308, 267–269
23. Poliakov, E., Gentleman, S., Cunningham, F. X., Jr., Miller-Ihli, N. J., and
Redmond, T. M. (2005) J. Biol. Chem. 280, 29217–29223
24. Hubbard, R., and Wald, G. (1952) J. Gen. Physiol. 36, 269–315
25. Reuter, T. (1964) Nature 204, 784–785
26. Fan, J., Rohrer, B., Moiseyev, G., Ma, J. X., and Crouch, R. K. (2003) Proc.
Natl. Acad. Sci. U.S.A. 100, 13662–13667
27. Driessen, C. A., Winkens, H. J., Hoffmann, K., Kuhlmann, L. D., Janssen,
B. P., Van Vugt, A. H., Van Hooser, J. P., Wieringa, B. E., Deutman, A. F.,
Palczewski, K., Ruether, K., and Janssen, J. J. (2000) Mol. Cell Biol. 20,
4275–4287
Acknowledgment—We thank Dr. John Saari for the gift of mouse
monoclonal antibody to CRALBP.
28. Maeda, A., Maeda, T., Imanishi, Y., Golczak, M., Moise, A. R., and Palcze-
wski, K. (2006) Biochemistry 45, 4210–4219
REFERENCES
29. Deigner, P. S., Law, W. C., Can˜ada, F. J., and Rando, R. R. (1989) Science
244, 968–971
1. Saari, J. C. (2000) Invest. Ophthalmol. Vis. Sci. 41, 337–348
2. Lamb, T. D., and Pugh, E. N., Jr. (2004) Prog. Retin. Eye Res. 23, 307–380
3. Moiseyev, G., Crouch, R. K., Goletz, P., Oatis, J., Jr., Redmond, T. M., and
Ma, J. X. (2003) Biochemistry 42, 2229–2238
30. Rando, R. R. (1991) Biochemistry 30, 595–602
31. Carlson, A., and Bok, D. (1992) Biochemistry 31, 9056–9062
32. Stecher, H., Gelb, M. H., Saari, J. C., and Palczewski, K. (1999) J. Biol.
Chem. 274, 8577–8585
4. Gollapalli, D. R., and Rando, R. R. (2003) Biochemistry 42, 5809–5818
5. Hamel, C. P., Tsilou, E., Pfeffer, B. A., Hooks, J. J., Detrick, B., and Red- 33. Winston, A., and Rando, R. R. (1998) Biochemistry 37, 2044–2050
mond, T. M. (1993) J. Biol. Chem. 268, 15751–15757
6. Jin, M., Li, S., Moghrabi, W. N., Sun, H., and Travis, G. H. (2005) Cell 122,
449–459
7. Moiseyev, G., Chen, Y., Takahashi, Y., Wu, B. X., and Ma, J. X. (2005) Proc.
Natl. Acad. Sci. U.S.A. 102, 12413–12418
34. Kuksa, V., Imanishi, Y., Batten, M., Palczewski, K., and Moise, A. R. (2003)
Vision Res. 43, 2959–2981
35. McBee, J. K., Kuksa, V., Alvarez, R., de Lera, A. R., Prezhdo, O., Haeseleer,
F., Sokal, I., and Palczewski, K. (2000) Biochemistry 39, 11370–11380
36. Landers, G. M., and Olson, J. A. (1988) J. Chromatogr. 438, 383–392
8. Redmond, T. M., Poliakov, E., Yu, S., Tsai, J. Y., Lu, Z., and Gentleman, S. 37. Wingerath, T., Kirsch, D., Spengler, B., and Stahl, W. (1999) Analyt. Bio-
(2005) Proc. Natl. Acad. Sci. U.S.A. 102, 13658–13663
9. Redmond, T. M., Yu, S., Lee, E., Bok, D., Hamasaki, D., Chen, N., Goletz, P., 38. Schu¨ttelkopf, A. W., and van Aalten, D. M. F. (2004) Acta Crystallogr. D
Ma, J. X., Crouch, R. K., and Pfeifer, K. (1998) Nat. Genet. 20, 344–351 Biol. Crystallogr. 60, 1355–1363
chem. 272, 232–242
10. Gu, S. M., Thompson, D. A., Srikumari, C. R., Lorenz, B., Finckh, U., 39. Redmond, T. M., Weber, C. H., Poliakov, E., Yu, S., and Gentleman, S.
Nicoletti, A., Murthy, K. R., Rathmann, M., Kumaramanickavel, G., Den-
ton, M. J., and Gal, A. (1997) Nat. Genet. 17, 194–197
(2007) Mol. Vis. 13, 1813–1821
40. Lorenz, B., Poliakov, E., Schambeck, M., Friedburg, C., Preising, M. N., and
Redmond, T. M. (2008) Invest. Ophthalmol. Vis. Sci. 49, 5235–5242
11. Marlhens, F., Bareil, C., Griffoin, J. M., Zrenner, E., Amalric, P., Eliaou, C.,
Liu, S. Y., Harris, E., Redmond, T. M., Arnaud, B., Claustres, M., and 41. Rando, R. R., and Chang, A. (1983) J. Am. Chem. Soc. 105, 2879–2882
Hamel, C. P. (1997) Nat. Genet. 17, 139–141
42. Can˜ada, F. J., Law, W. C., Rando, R. R., Yamamoto, T., Derguini, F., and
Nakanishi, K. (1990) Biochemistry 29, 9690–9697
12. Morimura, H., Fishman, G. A., Grover, S. A., Fulton, A. B., Berson, E. L.,
and Dryja, T. P. (1998) Proc. Natl. Acad. Sci. U.S.A. 95, 3088–3093
13. Thompson, D. A., Gyu¨ru¨s, P., Fleischer, L. L., Bingham, E. L., McHenry,
43. Golczak, M., Kuksa, V., Maeda, T., Moise, A. R., and Palczewski, K. (2005)
Proc. Natl. Acad. Sci. U.S.A. 102, 8162–8167
C. L., Apfelstedt-Sylla, E., Zrenner, E., Lorenz, B., Richards, J. E., Jacobson, 44. Gru¨tter, C., Alonso, E., Chougnet, A., and Woggon, W. D. (2006) Ange-
S. G., Sieving, P. A., and Gal, A. (2000) Invest. Ophthalmol. Vis. Sci. 41,
4293–4299
14. Maguire, A. M., Simonelli, F., Pierce, E. A., Pugh, E. N., Jr., Mingozzi, F.,
Bennicelli, J., Banfi, S., Marshall, K. A., Testa, F., Surace, E. M., Rossi, S.,
Lyubarsky, A., Arruda, V. R., Konkle, B., Stone, E., Sun, J., Jacobs, J.,
wandte Chemie 45, 1126–1130
45. Jenson, C., and Jorgensen, W. L. (1997) J. Am. Chem. Soc. 119,
10846–10854
46. Lesburg, C. A., Caruthers, J. M., Paschall, C. M., and Christianson, D. W.
(1998) Curr. Opin. Struct. Biol. 8, 695–703
Dell’Osso, L., Hertle, R., Ma, J. X., Redmond, T. M., Zhu, X., Hauck, B., 47. Bouvier, F., d’Harlingue, A., and Camara, B. (1997) Arch. Biochem. Bio-
Zelenaia, O., Shindler, K. S., Maguire, M. G., Wright, J. F., Volpe, N. J.,
phys. 346, 53–64
McDonnell, J. W., Auricchio, A., High, K. A., and Bennett, J. (2008) 48. Dougherty, D. A. (1996) Science 271, 163–168
N. Engl. J. Med. 358, 2240–2248
49. Mecozzi, S., West, A. P., Jr., and Dougherty, D. A. (1996) Proc. Natl. Acad.
15. Bainbridge, J. W., Smith, A. J., Barker, S. S., Robbie, S., Henderson, R.,
Balaggan, K., Viswanathan, A., Holder, G. E., Stockman, A., Tyler, N.,
Petersen-Jones, S., Bhattacharya, S. S., Thrasher, A. J., Fitzke, F. W., Carter,
Sci. U.S.A. 93, 10566–10571
50. Borowski, T., Blomberg, M. R., and Siegbahn, P. E. (2008) Chemistry 14,
2264–2276
B. J., Rubin, G. S., Moore, A. T., and Ali, R. R. (2008) N. Engl. J. Med. 358, 51. Klinman, J. P. (2006) J. Biol. Chem. 281, 3013–3016
2231–2239
52. Prigge, S. T., Eipper, B. A., Mains, R. E., and Amzel, L. M. (2004) Science
16. Cideciyan, A. V., Aleman, T. S., Boye, S. L., Schwartz, S. B., Kaushal, S.,
Roman, A. J., Pang, J. J., Sumaroka, A., Windsor, E. A., Wilson, J. M., Flotte,
304, 864–867
53. Kovaleva, E. G., and Lipscomb, J. D. (2007) Science 316, 453–457
T. R., Fishman, G. A., Heon, E., Stone, E. M., Byrne, B. J., Jacobson, S. G., 54. Holliday, G. L., Mitchell, J. B., and Thornton, J. M. (2009) J. Mol. Biol. 390,
and Hauswirth, W. W. (2008) Proc. Natl. Acad. Sci. U.S.A. 105,
560–577
15112–15117
55. Pienta, N. J., and Kessler, R. J. (1992) J. Am. Chem. Soc. 114, 2419–2428
17. Paik, J., During, A., Harrison, E. H., Mendelsohn, C. L., Lai, K., and Blaner, 56. Gurzadyan, G. G., Reynisson, J., and Steenken, S. (2007) Phys. Chem.
W. S. (2001) J. Biol. Chem. 276, 32160–32168
Chem. Phys. 9, 288–298
JANUARY 15, 2010•VOLUME 285•NUMBER 3
JOURNAL OF BIOLOGICAL CHEMISTRY 1927