Posttranslational Modifications of the Photoreceptor-Specific ABC Transporter ABCA4
Open accessAbstract
ABCA4 is a photoreceptor-specific ATP-binding cassette transporter implicated in the clearance of all-trans-retinal produced in the retina during light perception. Multiple mutations in this protein have been linked to Stargardt disease and other visual disorders. Here we report the first systematic study of posttranslational modifications in native ABCA4 purified from bovine rod outer segments. Seven N-glycosylation sites were detected in exocytoplasmic domains 1 and 2 by mass spectrometry, confirming the topological model of ABCA4 proposed previously. The modifying oligosaccharides were relatively short and homogeneous, predominantly representing a high-mannose type of N-glycosylation. Five phosphorylation sites were detected in cytoplasmic domain 1, with four of them located in the linker "regulatory-like" region conserved among ABCA subfamily members. Contrary to published results, phosphorylation of ABCA4 was found to be independent of light. Using human ABCA4 mutants heterologously expressed in mammalian cells, we showed that the Stargardt disease-associated alanine mutation in the phosphorylation site at position 901 led to protein misfolding and degradation. Furthermore, replacing the S1317 phosphorylation site reduced the basal ATPase activity of ABCA4, whereas an alanine mutation in either the S1185 or T1313 phosphorylation site resulted in a significant decrease in the all-trans-retinal-stimulated ATPase activity without affecting the basal activity, protein expression, or localization. In agreement with this observation, partial dephosphorylation of native bovine ABCA4 led to reduction of both basal and stimulated ATPase activity. Thus, we present the first evidence that phosphorylation of ABCA4 can regulate its function.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The overall topological model for ABCA4 is supported by glycosylation sites in both ECD domains and phosphorylation sites in CD1.
“The overall topological model for ABCA4 is supported by multiple glycosylation sites identified in both ECD domains, whereas CD1 hosts multiple phosphorylation sites.76,521,522”
From Chemistry of the Retinoid (Visual) Cycle (2014) · cites this paper as [521]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
EMBOSS: the European molecular biology open software suite.
Rice, P., Longden, I., & Bleasby, A. (2000) · Trends in Genetics · doi:10.1016/s0168-9525(00)02024-2 · Cited by 9,466 · see citing works
PEST sequences and regulation by proteolysis
RECHSTEINER, M. C., & Rogers, S. W. (1996) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(96)10031-1 · Cited by 1,645 · see citing works
Allikmets, R., Singh, N., Sun, H., Shroyer, N. F., Hutchinson, A., Chidambaram, A., Gerrard, B., Baird, L., Stauffer, D., Peiffer, A., et al. (1997) · Nature Genetics · doi:10.1038/ng0397-236 · Cited by 1,435 · see citing works
Weng, J., Mata, N. L., Azarian, S. M., Tzekov, R. T., Birch, D. G., & Travis, G. H. (1999) · Cell · doi:10.1016/s0092-8674(00)80602-9 · Cited by 881 · see citing works
Mutation of the Stargardt Disease Gene ( ABCR ) in Age-Related Macular Degeneration
Allikmets, R. L., Shroyer, N. F., Singh, N., Seddon, J. M., Lewis, R. A., Bernstein, P. S., Peiffer, A. P., Zabriskie, N. A., Li, Y., Hutchinson, A. A., et al. (1997) · Science · doi:10.1126/science.277.5333.1805 · Cited by 879 · see citing works
Mata, N. L., Weng, J., & Travis, G. H. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.130110497 · Cited by 456 · see citing works
Hamel, C. (2007) · Orphanet Journal of Rare Diseases · doi:10.1186/1750-1172-2-7 · Cited by 448 · see citing works
Retinitis pigmentosa caused by a homozygous mutation in the Stargardt disease gene ABCR
Martı́nez-Mir, A., Paloma, E., Allikmets, R. L., Ayuso, C., del Río, T., Dean, M. C., Vilageliu, L., Gonzàlez‐Duarte, R., & Balcells, S. (1998) · Nature Genetics · doi:10.1038/ng0198-11 · Cited by 401 · see citing works
Sun, H., Molday, R. S., & Nathans, J. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.12.8269 · Cited by 353 · see citing works
Self-citationRivera, A., White, K., Stöhr, H., Steiner, K., Hemmrich, N., Grimm, T., Jurklies, B., Lorenz, B., Scholl, H. P. N., Apfelstedt-Sylla, E., et al. (2000) · The American Journal of Human Genetics · doi:10.1086/303090 · Cited by 340 · see citing works
The 220-kDa Rim Protein of Retinal Rod Outer Segments Is a Member of the ABC Transporter Superfamily
Illing, M., Molday, L. L., & Molday, R. S. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.15.10303 · Cited by 304 · see citing works
Self-citationRetinopathy in Mice Induced by Disrupted All-trans-retinal Clearance
Maeda, A., Maeda, T., Golczak, M., & Palczewski, K. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m804505200 · Cited by 300 · see citing works
Self-citation[8] Preparation of retinal rod outer segments
Papermaster, D. S. (1982) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(82)81010-0 · Cited by 281 · see citing works
Wang, N., Chen, W., Linsel‐Nitschke, P., Martinez, L. O., Agerholm-Larsen, B., Silver, D. L., & Tall, A. R. (2003) · Journal of Clinical Investigation · doi:10.1172/jci16808 · Cited by 277 · see citing works
Swaroop, A., Chew, E. Y., Bowes Rickman, C., & Abecasis, G. R. (2009) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev.genom.9.081307.164350 · Cited by 270 · see citing works
ABCR expression in foveal cone photoreceptors and its role in Stargardt macular dystrophy
Molday, L. L., Rabin, A. R., & Molday, R. S. (2000) · Nature Genetics · doi:10.1038/77004 · Cited by 269 · see citing works
Self-citationStargardt's ABCR is localized to the disc membrane of retinal rod outer segments
Sun, H., & Nathans, J. (1997) · Nature Genetics · doi:10.1038/ng0997-15 · Cited by 251 · see citing works
Involvement of All-trans-retinal in Acute Light-induced Retinopathy of Mice
Maeda, A., Maeda, T., Golczak, M., Chou, S., Desai, A., Hoppel, C. L., Matsuyama, S., & Palczewski, K. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m900322200 · Cited by 248 · see citing works
Self-citationPapermaster, D. S., Schneider, B., Zorn, M., & Kraehenbühl, J. P. (1978) · The Journal of Cell Biology · doi:10.1083/jcb.78.2.415 · Cited by 237 · see citing works
Wang, N., Chen, W., Linsel‐Nitschke, P., et al. (2003) · Journal of Clinical Investigation · doi:10.1172/jci200316808 · Cited by 231 · see citing works
Mata, N. L., Tzekov, R. T., Liu, X., Weng, J., Birch, D. G., & Travis, G. H. (2001) · PubMed · Cited by 219 · see citing works
N-glycosylation and deletion mutants of the human MDR1 P-glycoprotein.
Schinkel, A. H., Kemp, S., Dollé, M. E. T., Rudenko, G., & Wagenaar, E. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)53199-9 · Cited by 214 · see citing works
Membrane Topology and Glycosylation of the Human Multidrug Resistance-associated Protein
Bakos, É., Hegedűs, T., Holló, Z., Welker, E., Tusnády, G., Zaman, G. J. R., Flens, M. J., Váradi, A., & Sarkadi, B. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.21.12322 · Cited by 211 · see citing works
Three-dimensional architecture of murine rod outer segments determined by cryoelectron tomography
Nickell, S., Park, P. S.-H., Baumeister, W., & Palczewski, K. (2007) · The Journal of Cell Biology · doi:10.1083/jcb.200612010 · Cited by 209 · see citing works
Self-citationBiochemical defects in ABCR protein variants associated with human retinopathies
Sun, H., Smallwood, P. M., & Nathans, J. (2000) · Nature Genetics · doi:10.1038/79994 · Cited by 203 · see citing works
Tsybovsky, Y., Molday, R. S., & Palczewski, K. (2010) · Advances in Experimental Medicine and Biology · doi:10.1007/978-1-4419-5635-4_8 · Cited by 200 · see citing works
Self-citationAn analysis of allelic variation in the ABCA4 gene.
Webster, A. R., Héon, E., Lotery, A. J., Vandenburgh, K., Casavant, T. L., Oh, K. T., Beck, G. E., Fishman, G. A., Lam, B. L., Levin, A. V., et al. (2001) · PubMed · Cited by 199 · see citing works
Phospholipid meets all-trans-retinal: the making of RPE bisretinoids
Sparrow, J. R., Wu, Y., Kim, C. Y., & Zhou, J. (2010) · Journal of Lipid Research · doi:10.1194/jlr.r000687 · Cited by 193 · see citing works
Phosphorylation of a Pest Sequence in ABCA1 Promotes Calpain Degradation and Is Reversed by ApoA-I
Martinez, L. O., Agerholm-Larsen, B., Wang, N., Chen, W., & Tall, A. R. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m307161200 · Cited by 186 · see citing works
ABCA4 disease progression and a proposed strategy for gene therapy
Cideciyan, A. V., Swider, M., Aleman, T. S., Tsybovsky, Y., Schwartz, S. B., Windsor, E. A. M., Roman, A. J., Sumaroka, A., Steinberg, J. D., Jacobson, S. G., et al. (2009) · Human Molecular Genetics · doi:10.1093/hmg/ddn421 · Cited by 186 · see citing works
Self-citationMolday, R. S., Zhong, M., & Quazi, F. (2009) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2009.02.004 · Cited by 182 · see citing works
Self-citationKey enzymes of the retinoid (visual) cycle in vertebrate retina
Kiser, P. D., Golczak, M., Maeda, A., & Palczewski, K. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2011.03.005 · Cited by 177 · see citing works
Self-citationBeharry, S., Zhong, M., & Molday, R. S. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m405216200 · Cited by 174 · see citing works
Self-citationRetinol dehydrogenases (RDHs) in the visual cycle
Parker, R. O., & Crouch, R. K. (2010) · Experimental Eye Research · doi:10.1016/j.exer.2010.08.013 · Cited by 173 · see citing works
Bungert, S., Molday, L. L., & Molday, R. S. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m101902200 · Cited by 173 · see citing works
Self-citationSwaroop, A., Branham, K. E., Chen, W., & Abecasis, G. (2007) · Human Molecular Genetics · doi:10.1093/hmg/ddm212 · Cited by 173 · see citing works
Azarian, S. M., & Travis, G. H. (1997) · FEBS Letters · doi:10.1016/s0014-5793(97)00517-6 · Cited by 170 · see citing works
Radu, R. A., Mata, N. L., Bagla, A., & Travis, G. H. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0308302101 · Cited by 167 · see citing works
Rich, D. P., Berger, H. A., Cheng, S. H., et al. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(20)80723-6 · Cited by 149 · see citing works
Redundant and unique roles of retinol dehydrogenases in the mouse retina
Maeda, A., Maeda, T., Sun, W., Zhang, H., Baehr, W., & Palczewski, K. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0707477104 · Cited by 131 · see citing works
Self-citationAhn, J., Wong, J. T., & Molday, R. S. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m000555200 · Cited by 130 · see citing works
Self-citationPeelman, F., Labeur, C., Vanloo, B., Roosbeek, S., Devaud, C., Duverger, N., Denèfle, P., Rosier, M., Vandekerckhove, J. S., & Rosseneu, M. (2002) · Journal of Molecular Biology · doi:10.1016/s0022-2836(02)01105-1 · Cited by 128 · see citing works
See, R. H., Caday‐Malcolm, R. A., Singaraja, R. R., Zhou, S., Silverston, A., Huber, M. T., Moran, J., James, E. R., Janoo, R. T. K., Savill, J. M., et al. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m204923200 · Cited by 127 · see citing works
Fitzgerald, M. L., Mendez, A. J., Moore, K. J., et al. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m100474200 · Cited by 121 · see citing works
Wiszniewski, W. K., Zaremba, C. M., Yatsenko, A. N., Jamrich, M., Wensel, T. G., Lewis, R. A., & Lupski, J. R. (2005) · Human Molecular Genetics · doi:10.1093/hmg/ddi310 · Cited by 108 · see citing works
Molday, R. S. (2007) · Journal of Bioenergetics and Biomembranes · doi:10.1007/s10863-007-9118-6 · Cited by 101 · see citing works
Self-citationThe gene for Stargardt disease, ABCA4, is a major retinal gene: a mini-review
Koenekoop, R. K. (2003) · Ophthalmic Genetics · doi:10.1076/opge.24.2.75.13996 · Cited by 97 · see citing works
Sun, H., & Nathans, J. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m010152200 · Cited by 93 · see citing works
Limited Roles of Rdh8, Rdh12, and Abca4 in all- trans -Retinal Clearance in Mouse Retina
Maeda, A., Golczak, M., Maeda, T., & Palczewski, K. (2009) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.09-3944 · Cited by 92 · see citing works
Self-citationRegulation of ABC Transporter Function Via Phosphorylation by Protein Kinases
Stolarczyk, E. I., Reiling, C. J., & Paumi, C. M. (2011) · Current Pharmaceutical Biotechnology · doi:10.2174/138920111795164075 · Cited by 71 · see citing works
Papermaster, D. S., Reilly, P., & Schneider, B. G. (1982) · Vision Research · doi:10.1016/0042-6989(82)90204-8 · Cited by 70 · see citing works
Roosbeek, S., Peelman, F., Verhee, A., Labeur, C., Caster, H., Lensink, M. F., Cirulli, C., Grooten, J., Cochet, C., Vandekerckhove, J. S., et al. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m401821200 · Cited by 69 · see citing works
Zhong, M., Molday, L. L., & Molday, R. S. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m806580200 · Cited by 66 · see citing works
Self-citationPeterman, S. M., & Mulholland, J. J. (2006) · Journal of the American Society for Mass Spectrometry · doi:10.1016/j.jasms.2005.10.008 · Cited by 64 · see citing works
Shiose, S., Chen, Y., Okano, K., Roy, S., Kohno, H., Tang, J. C. O., Pearlman, E. M., Maeda, T., Palczewski, K., & Maeda, A. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.228551 · Cited by 64 · see citing works
Self-citationEffects of phosphorylation of P-glycoprotein on multidrug resistance
Germann, U. A., Chambers, T. C., Ambudkar, S. V., et al. (1995) · Journal of Bioenergetics and Biomembranes · doi:10.1007/bf02110331 · Cited by 63 · see citing works
Valverde, D., Riveiro-Álvarez, R., Bernal, S., Jaakson, K., Baiget, M., Navarro, R., & Ayuso, C. (2006) · PubMed · Cited by 57 · see citing works
Stargardt's Disease and the ABCR Gene
Westerfeld, C. B., & Mukai, S. (2008) · Seminars in Ophthalmology · doi:10.1080/08820530701745249 · Cited by 39 · see citing works
ABCR expression in foveal cone photoreceptors and its role in Stargardt macular dystrophy
Molday, L. L., Rabin, A. R., & Molday, R. S. (2000) · American Journal of Ophthalmology · doi:10.1016/s0002-9394(00)00756-x · Cited by 39 · see citing works
Self-citationSpectrum of the ABCA4 Gene Mutations Implicated in Severe Retinopathies in Spanish Patients
Valverde, D., Riveiro-Álvarez, R., Aguirre-Lambán, J., Baiget, M., Carballo, M., Antiñolo, G., n, J. M. M., Sandoval, B. G., & Ayuso, C. (2007) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.06-0307 · Cited by 39 · see citing works
A method to determine the ionization efficiency change of peptides caused by phosphorylation
Gao, Y., & Wang, Y. (2007) · Journal of the American Society for Mass Spectrometry · doi:10.1016/j.jasms.2007.08.010 · Cited by 30 · see citing works
Aguirre-Lambán, J., Riveiro-Álvarez, R., Maia-Lopes, S., Cantalapiedra, D., Vallespín, E., Avila-Fernandez, A., Villaverde-Montero, C., Trujillo-Tiebas, M. J., Ramos, C., & Ayuso, C. (2008) · British Journal of Ophthalmology · doi:10.1136/bjo.2008.145193 · Cited by 29 · see citing works
Light stimulates phosphorylation of two large membrane proteins in frog photoreceptors
Szuts, E. Z. (1985) · Biochemistry · doi:10.1021/bi00336a054 · Cited by 25 · see citing works
Bereta, G. P., Wang, B., Kiser, P. D., Baehr, W., Jang, G.-F., & Palczewski, K. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.061713 · Cited by 23 · see citing works
Self-citationHa, B., Rich, D. P., Sh, C., et al. (1994) · PubMed · Cited by 23 · see citing works
Focus on Molecules: ABCA4 (ABCR) – An import-directed photoreceptor retinoid flipase
Sullivan, J. M. (2009) · Experimental Eye Research · doi:10.1016/j.exer.2009.03.005 · Cited by 21 · see citing works
An ATP-binding Cassette Transporter Is a Major Glycoprotein of Sea Urchin Sperm Membranes
Mengerink, K. J., & Vacquier, V. D. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m207184200 · Cited by 20 · see citing works
Chambers, T. C., Germann, U. A., Gottesman, M. M., et al. (1995) · Biochemistry · doi:10.1021/bi00043a021 · Cited by 17 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Chemistry of the Retinoid (Visual) Cycle
Kiser, P. D., Golczak, M., & Palczewski, K. (2014) · Chemical Reviews · doi:10.1021/cr400107q · Cited by 353 · see citing works
Self-citationChen, Y., Okano, K., Maeda, T., Chauhan, V., Golczak, M., Maeda, A., & Palczewski, K. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.315432 · Cited by 229 · see citing works
Self-citationStructure and function of ABCA4 and its role in the visual cycle and Stargardt macular degeneration
Molday, R. S., Garces, F. A., Scortecci, J. F., & Molday, L. L. (2022) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2021.101036 · Cited by 107 · see citing works
Self-citationRetinal Photodamage Mediated by All‐<i>trans</i>‐retinal<sup>†</sup>
Maeda, T., Golczak, M., & Maeda, A. (2012) · Photochemistry and Photobiology · doi:10.1111/j.1751-1097.2012.01143.x · Cited by 92 · see citing works
McClements, M. E., Barnard, A. R., Singh, M. S., Charbel Issa, P., Jiang, Z., Radu, R. A., & MacLaren, R. E. (2019) · Human Gene Therapy · doi:10.1089/hum.2018.156 · Cited by 92 · see citing works
Tsybovsky, Y., Orban, T., Molday, R. S., Taylor, D., & Palczewski, K. (2013) · Structure · doi:10.1016/j.str.2013.03.001 · Cited by 53 · see citing works
Self-citation
- Authors
- Tsybovsky, Y., Wang, B., Quazi, F., Molday, R. S., & Palczewski, K.
- Affiliations
- Case Western Reserve University (US)
- University of British Columbia (CA)
- Corresponding author
- Palczewski, Krzysztof
- Venue
- Biochemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2011-07-08
- Volume
- 50
- Issue
- 32
- Pages
- 6855-6866
- ISSN
- 0006-2960 (ISSN-L)
- 1520-4995
- PMC
- PMC3206228
- OpenAlex
- W2023815770
- Cited by
- 39
- References
- 68
- Citations by year
- 2025: 1 · 2024: 4 · 2022: 1 · 2021: 7 · 2020: 1 · 2019: 2 · 2018: 3 · 2017: 2 · 2015: 3 · 2014: 6 · 2013: 4 · 2012: 3
- FWCI
- 1.95
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Eye Institute (R01EY013203, R24EY021126, R01EY002422, P30EY011373, R01EY009339)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Keywords
- ABCA4, post-translational modification, N-glycosylation, phosphorylation, Stargardt disease, photoreceptors, rod outer segments, ATPase activity, protein misfolding, protein degradation, phosphorylation site mutation
- MeSH terms
- Adenosine Triphosphatases, Amino Acid Sequence, Animals, Carbohydrate Sequence, Cattle, Electrophoresis, Polyacrylamide Gel, Glycosylation, Humans, Mice, Inbred C57BL, Molecular Sequence Data, Phosphorylation, Protein Processing, Post-Translational, Rod Cell Outer Segment, ATP-Binding Cassette Transporters, Mice, Tandem Mass Spectrometry
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
