Ординатура / Офтальмология / Английские материалы / Eye, Retina, and Visual System of the Mouse_Chalupa, Williams_2008

Figure 59.2 Hypothetical schematic of the cone photoreceptor visual cycle. Transcellular diffusion and intracellular enzymatic processing of cone visual cycle retinoids are shown. Structure at left depicts a portion of the inner and outer segments of a cone photoreceptor cell. Structure at right depicts the apical end of a Müller

retinol, the product of the isomerohydrolase reaction, and relieve product inhibition of the enzyme. Proteomic analyses have been used to analyze protein components interacting with CRALBP. In one approach, a component with high affinity for CRALBP was detected with a gel overlay assay and identified as EBP50/NHERF-1 (ERM-binding phosphoprotein50/sodium-hydrogen exchanger regulatory factor 1) by mass spectrometric analysis of the corresponding component from a two-dimensional (2D) gel (Nawrot et al., 2004). EBP50/NHERF-1 is a multivalent organizer that can link various proteins with affinity for its two PDZ domains to the cytoskeleton via a C-terminal domain that binds ezrin, radixin, or moesin, proteins with affinity for actin (Bretscher et al., 2002). CRALBP, EBP50/NHERF-1, ezrin, and actin are all found in the apical processes of RPE cells, indi-

cell. The cells are joined by structures of the external limiting membrane (short wavy line). ARAT, acylCoA : retinol acyltransferase; HYDROLASE, 11-cis-retinyl ester hydrolase; ISOM, isomerase. See also the abbreviation key for figure 59.1. See color plate 69. (After Mata et al., 2002.)

cating the potential for interaction in vivo (Nawrot et al., 2004). EBP50/NHERF-1 may organize a retinoid-process- ing complex in the apical processes of RPE (Nawrot et al., 2006).

In a second proteomic approach, a preparation enriched in mouse RPE apical processes was isolated using wheat germ agglutinin-affinity chromatography, and protein components within it were identified using mass spectrometry (Bonilha et al., 2004a). Several visual cycle components were identified, including IRBP, CRALBP, EBP50/NHERF-1, CRBPI, 11-RDH, and ezrin. Furthermore, this approach, in combination with immunohistochemistry, allowed identification of more than 200 proteins from preparations of mouse RPE apical microvilli that may participate in the maintenance, support, and biochemical processes occurring

at this critical interface with photoreceptors (Bonilha et al., 2004b). These results support other studies providing evidence for a retinoid-processing complex in apical RPE.

In a third and ongoing approach, immunoprecipitation (IP) with or without iTRAQ quantitative mass spectrometric methods has been used to probe for visual cycle protein interactions in bovine RPE microsomes. IP experiments with the purified recombinant proteins RDH5 and CRALBP support a structural interaction in a C-terminal region of CRALBP (Wu et al., 2005). As noted earlier in the discussion of 11-cis-retinol dehydrogenase, several lines of evidence support a functional interaction between CRALBP and RDH5 (Saari and Bredberg, 1982; Saari et al., 1994; Golovleva et al., 2003). iTRAQ technology utilizes amine-specific tags and yields diagnostic reporter ions during MS/MS analysis of the labeled peptides, the intensity of which provides relative protein quantification. iTRAQ quantitative analysis of anti-CRALBP IP products from RPE microsomes supports a possible retinoid-processing protein complex composed of CRALBP, RPE65, LRAT, RDH5, and RGR (Gu et al., 2006). Comparative quantification of visual cycle reciprocal IP products is being used to further evaluate the composition of this putative RPE protein complex.

In other studies, proteomics has been instrumental in identifying posttranslational modifications and functional domains within visual cycle proteins. Two noteworthy examples include RPE65 and CRALBP. MALDI TOF mass spectrometric analyses of affinity purified RPE65 provided the first compelling evidence that RPE65 was posttranslationally modified and supported the presence in RPE of both a cytosolic, lower-mass isoform and a membrane-associated, higher-mass isoform (Ma et al., 2001). More recently, Rando and co-workers used mass spectrometry to characterize tryptic peptides from RPE65 and reported the presence of three palmitoylated cysteine residues in the membraneassociated isoform. They suggested that palmitoylation may serve as a switching mechanism controlling RPE65 lig- and-binding selectivity (Xue et al., 2004). However, others have reported that mutating these three cysteine residues has little effect on isomerase activity, so the role of posttranslational modifications in RPE65 functions remains to be determined (Redmond et al., 2005; Takahashi et al., 2006).

Photoaffinity labeling and proteomic high-resolution topological analyses have been particularly useful in understanding the functional domains of CRALBP involved in ligand and protein interactions (Z. Wu et al., 2004). Eight photoaffinity-modified residues in human CRALBP were identified by liquid chromatography tandem mass spectrometry, several of which had been independently identified using other protein chemical methods and site-directed mutagenesis. Topological analysis of apoand holo-CRALBP

by hydrogen-deuterium exchange and mass spectrometry demonstrated that residues 198–255 incorporated significantly less deuterium when the retinoid-binding pocket was occupied with 11-cis-retinal. This hydrophobic region encompasses all but one of the photolabeled residues. In a structural model of CRALBP based on the crystal structures of three CRAL_TRIO family members, all of the photolabeled residues lined the ligand-binding cavity except one, which appears to reside in a flexible loop at the entrance/ exit of the ligand cavity. The topological analyses also supported the solvent accessibility of CRALBP residues 147– 157 and 262–275 and are consistent with a positively charged groove in the structural model that may be involved in protein interactions as proposed for other CRAL_TRIO family members (Z. Wu et al., 2004).

Conclusion

The past decade has produced an astounding amount of information on the pathway for regeneration of rod visual pigments, thanks to advances in mouse genetics, genetic manipulation, and proteomics. The pathway for regeneration of cones has been more difficult to approach experimentally because of the relatively small proportion of cones in mouse and bovine retinas. Despite these great advances, much remains to be learned about rod visual pigment regeneration. For example, the molecular entities responsible for the dehydrogenase activities of the visual cycle remain to be assigned, and the cone pathway remains poorly understood. In addition, the cell biology of retinoid processing and transfer remains to be worked out. We expect many of these problems to be solved as increasingly clever ways of utilizing mouse genomics and proteomics evolve.

acknowledgments Work was supported by NIH grant nos. EY02317, EY06603, EY014239, and EY015638 and by Research to Prevent Blindness, Inc., Foundation Fighting Blindness, the Cleveland Clinic Foundation, and the Milton and Ruth Steinbach fund. The authors thank Gregory G. Garwin for help with the illustrations.

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CONTRIBUTORS

Badea, Tudor C. Johns Hopkins University Medical School, Baltimore, Maryland

Bear, Mark F. Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts

Berardi, Nicoletta Università di Firenze del Consiglio Nazionale delle Ricerche, Pisa, Italy

Berger, Wolfgang Division of Medical Molecular Genetics and Gene Diagnostics, Institute of Medical Genetics, University of Zurich, Zurich, Switzerland

Blankenship, Aaron G. Neurobiology Section, Division of Biological Sciences, University of California, La

ogy, New York University School of Medicine, New York, New York

Boye, Sanford L. Department of Ophthalmology and Molecular Genetics, University of Florida, Gainesville, Florida

Boye, Shannon E. Department of Ophthalmology and Molecular Genetics, University of Florida, Gainesville, Florida

Brown, Richard E. Department of Psychology, Dalhousie University, Nova Scotia, Canada

Burkhalter, Andreas Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri

Caspi, Rachel R. Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland

Cenni, Maria Cristina Istituto di Neuroscienze del Consiglio Nazionale delle Ricerche, Pisa, Italy

Cepko, Constance L. Department of Genetics, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts

Chalupa, Leo M. Section of Neurobiology, Physiology, and Behavior, University of California, Davis, California

Chang, Bo The Jackson Laboratory, Bar Harbor, Maine Chen, Chinfei Division of Neuroscience and Neurobiology Program, Children’s Hospital, Harvard Medical

School, Boston, Massachusetts

Clancy, Barbara Department of Biology, University of Central Arkansas, Conway, Arkansas

Coombs, Julie L. Section of Neurobiology, Physiology, and Behavior, University of California, Davis, California

Crabb, John W. Department of Ophthalmic Research, Cole Eye Institute, Cleveland, Ohio

Danciger, Michael Department of Biology, Loyola Marymount University, Los Angeles, California

Daniele, Lauren L. Department of Ophthalmology, F. M. Kirby Center for Molecular Ophthalmology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Dorrell, Michael I. Department of Cell Biology, Scripps Research Institute, La Jolla, California

Douglas, Robert M. Department of Ophthalmology and Vision Sciences, University of British Columbia, Vancouver, Canada

Dräger, Ursula C. Eunice Kennedy Shriver Center for Mental Retardation, University of Massachusetts Medical School, Waltham, Massachusetts

Dreher, Bogdan School of Medical Sciences and Bosch Institute, University of Sydney, Sydney, Australia

Dyer, Michael A. Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, Tennessee

Erskine, Lynda School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Aberdeen, Scotland

Feller, Marla B. Neurobiology Section, Division of Biological Sciences, University of California, Berkeley, California

Finlay, Barbara L. Department of Psychology, Cornell University, Ithaca, New York

Frenkel, Mikhail Y. Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts

Friedlander, Martin Department of Cell Biology, Scripps Research Institute, La Jolla, California

Galli-Resta, Lucia Istituto di Neuroscienze del Consiglio Nazionale delle Ricerche, Pisa, Italy

Geisert, Eldon E. Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, Tennessee

Goldberg, Jeffrey L. Bascom Palmer Eye Institute, University of Miami, Miami, Florida

Graw, Jochen Institute of Developmental Genetics, German Research Center for Environmental Health, Helmholtz Center Munich, Neuherberg, Germany

Gregg, Ronald G. Departments of Ophthalmology and Visual Sciences and Biochemistry and Molecular Biology, University of Louisville, Louisville, Kentucky

Grubb, Matthew S. Medical Research Council Centre for Developmental Neurobiology, King’s College London, London, England

Gubitosi-Klug, Rose A. Departments of Medicine and Ophthalmology, Case Western Reserve University, Cleveland, Ohio

Guido, William Department of Anatomy and Neurobiology, Virginia Commonweath University School of Medicine, Richmond, Virginia

Hauswirth, William W. Departments of Ophthalmology and Molecular Genetics, University of Florida, Gainesville, Florida

Hazlett, Linda D. Department of Anatomy/Cell Biology, Wayne State University School of Medicine, Detroit, Michigan

Hoehenwarter, Wolfgang Max Planck Institute for Infection Biology, Berlin, Germany

Hofer, Sonja B. Max Planck Institute of Neurobiology, Martinsried, Germany

Howell, Gareth R. The Jackson Laboratory, Bar Harbor, Maine

Hübener, Mark Max Planck Institute of Neurobiology, Martinsried, Germany

Isa, Tadashi Department of Developmental Physiology, National Institute for Physiological Sciences, Okazaki, Japan

Molecular Biology, University of Texas, Houston, Texas Lamba, Deepak University of Washington, School of

Medicine, Seattle, Washington

Leamey, Catherine A. School of Medical Sciences and Bosch Institute, University of Sydney, Sydney, Australia Luo, Tuanlian Eunice Kennedy Shriver Center for Mental Retardation, University of Massachusetts Medical

School, Waltham, Massachusetts

Lyubarsky, Arkady Department of Ophthalmology, F. M. Kirby Center for Molecular Ophthalmology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Maffei, Lamberto Istituto di Neuroscienze del Consiglio Nazionale delle Ricerche, Pisa, Italy

Marchant, Jeffrey K. Department of Anatomy and Cell Biology, Tufts University School of Medicine, Boston, Massachusetts

Mason, Carol A. Department of Pathology and Cell Biology, Center for Neurobiology and Behavior, Columbia University, New York, New York

Matsuda, Takahiko Department of Genetics and Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts

May, Christian-Albrecht Institut für Anatomie, Technological University of Dresden, Dresden, Germany

McCall, Maureen A. Department of Psychological and Brain Sciences, University of Louisville, Louisville, Kentucky

Mrsic-Flogel, Thomas D. Max Planck Institute of Neurobiology, Martinsried, Germany

Mu, Xiuqian Department of Biochemistry and Molecular Biology, University of Texas, Houston, Texas

Naggert, Juergen K. The Jackson Laboratory, Bar Harbor, Maine

Nathans, Jeremy Department of Molecular Biology and Genetics, Johns Hopkins University Medical School, Baltimore, Maryland

Nelson, Branden University of Washington, School of Medicine, Seattle, Washington

Nikonov, Sergei S. Department of Ophthalmology, F. M. Kirby Center for Molecular Ophthalmology, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

Nishina, Patsy M. The Jackson Laboratory, Bar Harbor, Maine

Panda, Satchidananda Regulatory Biology Laboratory, Salk Institute for Biological Studies, La Jolla, California

Parapuram, Sunil K. W. K. Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan

Peachey, Neal S. Cleveland Veterans Affairs Medical Center, Cleveland Clinic Foundation, Cleveland, Ohio Petros, Timothy J. Department of Pathology and Cell

Biology, Center for Neurobiology and Behavior, Columbia University, New York, New York

Piatigorsky, Joram Laboratory of Molecular and Developmental Biology, National Eye Institute, National Institutes of Health, Bethesda, Maryland

Pinto, Lawrence H. Department of Neurobiology and Physiology and Center for Functional Genomics, Northwestern University, Evanston, Illinois

Porciatti, Vittorio Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida

Powers, Michael R. Oregon Health and Science University, Portland, Oregon; Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida

Protti, Dario A. School of Medical Sciences and Bosch Institute, University of Sydney, Sydney, Australia

Prusky, Glen T. Department of Neuroscience, Canadian Centre for Behavioural Neuroscience, University of Lethbridge, Alberta, Canada

Pugh, Edward N., Jr. Department of Ophthalmology, F. M. Kirby Center for Molecular Ophthalmology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Reese, Benjamin E. Neuroscience Research Institute, University of California, Santa Barbara, California

Reh, Thomas A. Health Sciences Center, University of Washington, School of Medicine, Seattle, Washington Rice, Dennis S. Lexicon Pharmaceuticals, The Wood-

lands, Texas

Robinson, Michael L. Zoology Department, Miami University, Oxford, Ohio

Saari, John C. Department of Ophthalmology, University of Washington, Seattle, Washington

Sakatani, Tomoya Department of Developmental Physiology, National Institute for Physiological Sciences, Okazaki, Japan

Sale, Alessandro Scuola Normale Superiore, Laboratory of Neurobiology, Pisa, Italy

Schaeffel, Frank Section of Neurobiology of the Eye, University Eye Hospital Tübingen, Tübingen, Germany Sparrow, Janet R. Department of Ophthalmology,

Columbia University, New York, New York

Stahl, John S. Department of Neurology, Case Western Reserve University, Cleveland, Ohio

Stone, Jonathan Research School of Biological Sciences, Australian National University, Canberra City, Australia

Strettoi, Enrica Istituto di Neuroscienze del Consiglio Nazionale delle Ricerche, Laboratorio di Neurofisiologia,

ular and Developmental Biology, National Eye Institute, National Institutes of Health, Bethesda, Maryland

Swaroop, Anand Neurobiology Neurodegeneration and Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, Maryland; W. K. Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan

Tamm, Ernst R. Institute of Human Anatomy and Embryology, University of Regensburg, Regensburg, Germany

Thompson, Hannah Institute of Ophthalmology, University College London, London, England