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Cited by 200Retinal Development and DisordersDrug Transport and Resistance MechanismsRetinoids in leukemia and cellular processes

The ATP-Binding Cassette Transporter ABCA4: Structural and Functional Properties and Role in Retinal Disease

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Tsybovsky, Yaroslav, Molday, Robert S., Palczewski, Krzysztof·2010·Advances in Experimental Medicine and Biology
DOI 10.1007/978-1-4419-5635-4_8PMC PMC2930353
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Abstract

ATP-binding cassette transporters (ABC transporters) utilize the energy of ATP hydrolysis to translocate an unusually diverse set of substrates across cellular membranes. ABCA4, also known as ABCR, is a approximately 250 kDa single-chain ABC transporter localized to the disk margins of vertebrate photoreceptor outer segments. It is composed of two symmetrically organized halves, each comprising six membrane-spanning helices, a large glycosylated exocytoplasmic domain located inside the disk, and a cytoplasmic domain with an ATP-binding cassette. Hundreds of mutations in ABCA4 are known to cause impaired vision and blindness such as in Stargardt disease as well as related disorders. Biochemical and animal model studies in combination with patient analyses suggest that the natural substrate of ABCA4 is retinylidene-phosphatidylethanolamine (N-retinylidene-PE), a precursor of potentially toxic diretinal compounds. ABCA4 prevents accumulation of N-retinylidene-PE inside the disks by transporting it to the cytoplasmic side of the disk membrane where it can dissociate, allowing the released all-trans-retinal to enter the visual cycle. The pathogenesis of diseases caused by mutations in ABCA4 is complex, comprising a loss-of-function component as well as photoreceptor stress caused by protein mislocalization and misfolding.

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  • Human ABCA4 is an integral membrane protein of 2273 residues forming two homologous but nonidentical parts, each with six membrane-spanning helices, a cytoplasmic domain containing a nucleotide-binding site with Walker A and B motifs, and an exocytoplasmic domain.

    “Human ABCA4 is an integral membrane protein with 2273 residues that form two homologous but nonidentical parts. Each carries six membrane-spanning helices that constitute a TMD, a soluble cytoplasmic domain (CD) that hosts a canonical nucleotide-binding site (NBD) with Walker A and Walker B motifs characteristic of ATP-processing enzymes, and an exocytoplasmic (intradiscal) domain (ECD) (Figure 33”

    From Chemistry of the Retinoid (Visual) Cycle (2014) · cites this paper as [76]

    Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

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  • 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 [76]

    Section 4.3 says glycosylation studies support the placement of both exocytoplasmic domains, and section 4.4 reports eight glycosylation sites across those domains. But section 4.3 describes ABCA4 phosphorylation only as a possibility needing further study; it does not identify multiple phosphorylation sites in CD1. Page numbers are unavailable in our copy. (LLM, conf=0.88)

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  • ABCA4 protein is a 250 kDa flippase that transports all-trans-retinal across the photoreceptor membrane to the cytoplasmic side, making it an important part of the visual cycle and removal of toxic vitamin A products.

    “ABCA4 protein is a 250 kDa flippase, which transports all-trans-retinal, across the photoreceptor membrane to the cytoplasmic side, making it an important part of the visual cycle and removal of toxic vitamin A products [71,92].”

    From The Role of Vitamin A in Retinal Diseases (2022) · cites this paper as [92]

    The Abstract identifies ABCA4 as a ~250 kDa transporter and links its activity to the visual cycle and prevention of toxic compounds. Section 5.4 proposes that ABCA4 flips N-retinylidene-PE—not free all-trans-retinal—to the cytoplasmic side of the photoreceptor disk membrane, where the compound can dissociate and release all-trans-retinal. The citing sentence overstates both the substrate and the certainty of the transport mechanism. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • ATP-dependent transporters such as ABCA4 or the channel-like property of STRA6 could facilitate retinoid transport.

    “But this process could be facilitated by ATP-dependent transporters such as ABCA476,485−487 or the channel-like property of STRA6.488−492”

    From Chemistry of the Retinoid (Visual) Cycle (2014) · cites this paper as [76]

  • Most genes encoding retinoid cycle enzymes are associated with retinal disease.

    “Most of the genes encoding retinoid cycle enzymes are associated with retinal disease (Figure 36).64,76,77,285,547−552”

    From Chemistry of the Retinoid (Visual) Cycle (2014) · cites this paper as [76]

    Section 3, “ABCA4 and Vision Diseases,” links mutations in ABCA4 to several retinal disorders, while Section 5.4 describes ABCA4 as a transporter involved in the visual cycle. Neither passage says that most genes encoding retinoid-cycle enzymes are associated with retinal disease; searches for that broader claim and for visual-cycle enzyme disease associations found no supporting passage. (LLM, conf=0.75)

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Authors
Tsybovsky, Y., Molday, R. S., & Palczewski, K.
Affiliations
Case Western Reserve University (US)
Corresponding author
Tsybovsky, Yaroslav
ORCID
Venue
Advances in Experimental Medicine and Biology
Publisher
Springer New York
Published
2010
Volume
703
Pages
105-125
ISSN
0065-2598 (ISSN-L)
DOI
10.1007/978-1-4419-5635-4_8
PMC
PMC2930353
OpenAlex
W162823058
Cited by
200
References
87
Citations by year
2026: 6 · 2025: 10 · 2024: 15 · 2023: 12 · 2022: 17 · 2021: 9 · 2020: 17 · 2019: 12 · 2018: 9 · 2017: 15 · 2016: 12 · 2015: 16 · 2014: 13 · 2013: 10 · 2012: 12
FWCI
14.38
Type
book chapter
Language
en
Open access
Locations
  • Advances in experimental medicine and biology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Eye Institute (R01EY008123, EY 09339, EY 08123, R01EY002422, P30 EY-11373, 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, ABC transporters, photoreceptor outer segments, Stargardt disease, visual cycle, all-trans-retinal, retinal disease, protein misfolding, protein mislocalization, loss-of-function mutations
MeSH terms
Abnormalities, Multiple, Animals, Disease Models, Animal, Genes, Recessive, Humans, Macular Degeneration, Models, Biological, Models, Molecular, Mutation, Phosphatidylethanolamines, Protein Processing, Post-Translational, Retinal Diseases, Retinoids, Rod Cell Outer Segment, Protein Structure, Tertiary, Mice, Knockout, ATP-Binding Cassette Transporters, Amino Acid Motifs, Mice, Acrocallosal Syndrome, Agenesis of Corpus Callosum

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