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

Tsybovsky, Yaroslav; Molday, Robert S.; Palczewski, Krzysztof

doi:10.1007/978-1-4419-5635-4_8

Cited by 170 publications

(162 citation statements)

References 87 publications

(151 reference statements)

Supporting

Mentioning

160

Contrasting

Unclassified

Order By: Relevance

“…This localization is dictated by the exocytoplasmic domains (ECD) of ABCA4 (27). These domains are too large to fit within the luminal space between the flattened disk membranes but can fit in the space outlined by the rim region (12,27,28). It remains to be determined if the transport and clearance of 11-cisand all-trans-retinal from photoreceptors is further facilitated by the rim localization of ABCA4.…”

Section: Discussionmentioning

confidence: 99%

ATP-binding cassette transporter ABCA4 and chemical isomerization protect photoreceptor cells from the toxic accumulation of excess 11- cis -retinal

Quazi

Molday

2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

110

101

View full text Add to dashboard Cite

The visual cycle is a series of enzyme-catalyzed reactions which converts all-trans-retinal to 11-cis-retinal for the regeneration of visual pigments in rod and cone photoreceptor cells. Although essential for vision, 11-cis-retinal like all-trans-retinal is highly toxic due to its highly reactive aldehyde group and has to be detoxified by either reduction to retinol or sequestration within retinal-binding proteins. Previous studies have focused on the role of the ATP-binding cassette transporter ABCA4 associated with Stargardt macular degeneration and retinol dehydrogenases (RDH) in the clearance of all-trans-retinal from photoreceptors following photoexcitation. How rod and cone cells prevent the accumulation of 11-cis-retinal in photoreceptor disk membranes in excess of what is required for visual pigment regeneration is not known. Here we show that ABCA4 can transport N-11-cis-retinylidene-phosphatidylethanolamine (PE), the Schiff-base conjugate of 11-cis-retinal and PE, from the lumen to the cytoplasmic leaflet of disk membranes. This transport function together with chemical isomerization to its all-trans isomer and reduction to all-trans-retinol by RDH can prevent the accumulation of excess 11-cis-retinal and its Schiff-base conjugate and the formation of toxic bisretinoid compounds as found in ABCA4-deficient mice and individuals with Stargardt macular degeneration. This segment of the visual cycle in which excess 11-cis-retinal is converted to all-transretinol provides a rationale for the unusually high content of PE and its long-chain unsaturated docosahexaenoyl group in photoreceptor membranes and adds insight into the molecular mechanisms responsible for Stargardt macular degeneration.T he visual cycle plays a crucial role in the removal of all-transretinal from photoreceptor cells following photoexcitation and its conversion to 11-cis-retinal for the regeneration of visual pigments in rod and cone photoreceptor cells (1). Deficient clearance of all-trans-retinal and its Schiff-base conjugate N-retinylidenephosphatidylethanolamine (PE) from rod and cone photoreceptor outer segments results in condensation reactions which produce a mixture of bisretinoid products including the pyridinium bisretinoid compound A2PE and its hydrolytic product A2E (2, 3). These bisretinoid compounds accumulate as lipofuscin deposits in retinal pigment epithelial (RPE) cells upon phagocytosis of outer segments and have been implicated in the pathology of a number of retinal degenerative diseases. This is particularly evident in autosomal recessive Stargardt macular degeneration in which mutations in the ATP-binding cassette (ABC) transporter ABCA4 which impair the N-retinylidene-PE transport activity of ABCA4 cause a buildup of lipofuscin, atrophy of the central retina, and severe progressive loss in vision (4-8).In initial studies, Abca4 knockout mice were reported to show a light-dependent accumulation of all-trans-retinal, PE, and N-retinylidene-PE in photoreceptors and lipofuscin and A2E in RPE (9). This led to a model...

show abstract

Section: Discussionmentioning

confidence: 99%

ATP-binding cassette transporter ABCA4 and chemical isomerization protect photoreceptor cells from the toxic accumulation of excess 11- cis -retinal

Quazi

Molday

2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

110

101

View full text Add to dashboard Cite

show abstract

“…Does this mean that Cdr3p and ABCB4 present an "importer" fold in contrast to their homologues, Cdr1p and ABCA4, respectively, which would be predicted to present "exporter" folds? Membrane span predictions and whole sequence homology show that the architecture for these importers is not compliant with the bacterial importer type but, notably, ABCA4 contains a conserved EAA amino acid motif that is a signature for bacterial ABC importers [61,67]. It is possible that eukaryotic ABC "importers" present the same fold as "exporters", but have evolved an inverse affinity switch that allow them to transport the substrate inwards.…”

Section: General Structural Features Of Abc Transportersmentioning

confidence: 99%

Structure and mechanism of ATP-dependent phospholipid transporters

López‐Marqués

Poulsen

Bailly

et al. 2015

Biochimica et Biophysica Acta (BBA) - General Subjects

View full text Add to dashboard Cite

Background: ATP-binding cassette (ABC) transporters and P4-ATPases are two large and seemingly unrelated families of primary active pumps involved in moving phospholipids from one leaflet of a biological membrane to the other. Scope of review: This review aims to identify common mechanistic features in the way phospholipid flipping is carried out by two evolutionarily unrelated families of transporters. Major conclusions: Both protein families hydrolyze ATP, although they employ different mechanisms to use it, and have a comparable size with twelve transmembrane segments in the functional unit. Further, despite differences in overall architecture, both appear to operate by an alternating access mechanism and during transport they might allow access of phospholipids to the internal part of the transmembrane domain. The latter feature is obvious for ABC transporters, but phospholipids and other hydrophobic molecules have also been found embedded in P-type ATPase crystal structures. Taken together, in two diverse groups of pumps, nature appears to have evolved quite similar ways of flipping phospholipids. General significance: Our understanding of the structural basis for phospholipid flipping is still limited but it seems plausible that a general mechanism for phospholipid flipping exists in nature. This article is part of a Special Issue entitled Structural biochemistry and biophysics of membrane proteins.

show abstract

“…These genetically modified mice lack both the ATP-binding cassette transporter 4 (ABCA4) and the all-trans-retinol (ROL) dehydrogenase enzyme (RDH8). Both proteins are involved in the retinoid cycle, a metabolic sequence of chemical transformations needed to maintain continuous regeneration of the visual chromophore, 11−cis−retinal (11cRAL) from all-trans-retinal (atRAL), and both are also required for efficient clearance of atRAL upon its liberation from activated rhodopsin (13)(14)(15)(16)(17). Impaired clearance of atRAL is detrimental to retinal cells due to the high toxicity of this reactive aldehyde to all cell types (18).…”

mentioning

confidence: 99%

Two-photon microscopy reveals early rod photoreceptor cell damage in light-exposed mutant mice

Maeda

Palczewska

Golczak³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Atrophic age-related and juvenile macular degeneration are especially devastating due to lack of an effective cure. Two retinal cell types, photoreceptor cells and the adjacent retinal pigmented epithelium (RPE), reportedly display the earliest pathological changes. Abca4 −/− Rdh8 −/− mice, which mimic many features of human retinal degeneration, allowed us to determine the sequence of light-induced events leading to retinal degeneration. Using two-photon microscopy with 3D reconstruction methodology, we observed an initial strong retinoid-derived fluorescence and expansion of Abca4 −/− Rdh8 −/− mouse rod cell outer segments accompanied by macrophage infiltration after brief exposure of the retina to bright light. Additionally, light-dependent fluorescent compounds produced in rod outer segments were not transferred to the RPE of mice genetically defective in RPE phagocytosis. Collectively, these findings suggest that for light-induced retinopathies in mice, rod photoreceptors are the primary site of toxic retinoid accumulation and degeneration, followed by secondary changes in the RPE.

show abstract

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

Cited by 170 publications

References 87 publications

ATP-binding cassette transporter ABCA4 and chemical isomerization protect photoreceptor cells from the toxic accumulation of excess 11- cis -retinal

ATP-binding cassette transporter ABCA4 and chemical isomerization protect photoreceptor cells from the toxic accumulation of excess 11- cis -retinal

Structure and mechanism of ATP-dependent phospholipid transporters

Two-photon microscopy reveals early rod photoreceptor cell damage in light-exposed mutant mice

Contact Info

Product

Resources

About