Review
The role of the photoreceptor ABC transporter ABCA4 in lipid transport and Stargardt macular degeneration

https://doi.org/10.1016/j.bbalip.2009.02.004Get rights and content

Abstract

ABCA4 is a member of the ABCA subfamily of ATP binding cassette (ABC) transporters that is expressed in rod and cone photoreceptors of the vertebrate retina. ABCA4, also known as the Rim protein and ABCR, is a large 2273 amino acid glycoprotein organized as two tandem halves, each containing a single membrane spanning segment followed sequentially by a large exocytoplasmic domain, a multispanning membrane domain and a nucleotide binding domain. Over 500 mutations in the gene encoding ABCA4 are associated with a spectrum of related autosomal recessive retinal degenerative diseases including Stargardt macular degeneration, cone–rod dystrophy and a subset of retinitis pigmentosa. Biochemical studies on the purified ABCA4 together with analysis of abca4 knockout mice and patients with Stargardt disease have implicated ABCA4 as a retinylidene-phosphatidylethanolamine transporter that facilitates the removal of potentially reactive retinal derivatives from photoreceptors following photoexcitation. Knowledge of the genetic and molecular basis for ABCA4 related retinal degenerative diseases is being used to develop rationale therapeutic treatments for this set of disorders.

Introduction

The transport of lipids across biological membranes is critical for the structure, function and survival of cells. This process is typically carried out by a variety of integral membrane proteins which specifically bind and actively or passively translocate lipids across the membrane lipid bilayer. Some lipid transporters import or export lipids from cells or intracellular organelles, while others simply flip lipids such as phospholipids across the lipid bilayer to generate or maintain transbilayer lipid asymmetry critical for cell membrane structure and function [1]. Lipid substrates known to be transported across membranes include vitamins, fatty acids, phospholipids, glycolipids, cholesterol, bile salts, steroids, toxins, drugs, and metabolites.

ATP binding cassette (ABC) transporters comprise a large superfamily of proteins found in essentially all living organisms [2]. The human genome encodes 48 ABC transporters which have been organized into 7 subfamilies designated ABCA through ABCG [3]. A significant number of ABC transporters function in lipid trafficking in cells and many have been linked to severe genetic diseases [4], [5]. For example, inherited defects in ALD (ABCD1), a transporter of very long chain fatty acids, is associated with adrenoleukodystrophy [6], defects in Sterolin1 and 2 (ABCG5/ABCG8), transporters for sterols, have been linked to sitosterolemia [7], defects in ABC1 (ABCA1) which mediate the efflux of cholesterol and phospholipid from cells cause Tangier disease [8], and defects in MDR3 and BSEP (ABCB11) involved in the transport of phosphatidylcholine and bile acids, respectively, are known to cause liver disease [9], [10].

Members of the ABCA subfamily of ABC transporters have been implicated in the transport of various lipids across cell membranes [5]. Of these, four ABCA transporters are now known to be associated with a various genetic disorders that result from defects in lipid transport. In this review, we will focus on the biochemical properties of one of these transporters, ABCA4, and its role in lipid transport and retinal degenerative diseases associated with severe vision loss.

Section snippets

ABCA subfamily of ABC transporters

The ABCA subfamily of ATP binding cassette transporters is a group of ABC transporters having a relatively high degree of sequence identity and a similar structural organization. Twelve ABCA genes designated ABCA1ABCA13 have been identified in the human genome [5], [11]. ABCA11 is now known to be a pseudogene and therefore is no longer considered as a member of this subfamily. Two subgroups have been identified. One comprises a cluster of genes (ABCA5, ABCA6, ABCA8, ABCA9, and ABCA10) that map

Cellular localization and structural features of ABCA4

ABCA4 was first cloned in 1997 using two different strategies. In one approach, the gene for the Rim protein, an abundant high molecular weight photoreceptor membrane protein of unknown function first described in the late 1970's, was cloned and shown to encode a novel photoreceptor ATP binding cassette protein [14], [26], [27]. In another approach, Allikmets and coworkers identified the gene defective in Stargardt disease, a relatively common, early onset macular dystrophy [28], [29]. This

ATP binding and hydrolysis

Specific binding of nucleotides to ABCA4 was first demonstrated using photoaffinity labeling techniques. The photoreactive 8-azido ATP or 8-azido ADP covalently labeled purified ABCA4 or ABCA4 in photoreceptor membranes upon irradiation with UV light [14]. Excess unlabeled ATP or GTP inhibited 8-azido ATP labeling indicating that the labeled nucleotide binding site of ABCA4 can accommodate either adenine or guanine nucleotides. When photoaffinity labeled ABCA4 in photoreceptor membranes was

Transport mechanism

On the basis of biochemical studies and structural analysis, a general scheme has been proposed for the transport of substrates across membranes by ABC transporters [46], [65], [66], [67], [68]. In the initial step, the substrate binds to a high affinity site within the transmembrane domain (TMD) of the ABC transporter. This induces a protein conformational change which alters the affinity of the NBDs for ATP. The binding of ATP causes the NBDs to come in close contact with each ATP present in

Analysis of ABCA4 knockout mice

The role of ABCA4 as an N-retinylidene-PE transporter has also been proposed from studies of abca4 knockout mice [70], [71], [72] (Fig. 6). The photoreceptor cells of the abca4 deficient mice exhibit a normal appearance with well-organized outer segments. This suggests that ABCA4 is not directly involved in outer segment morphogenesis or structure. Likewise, the photoresponse of these mice is normal except for relatively small changes in the recovery of the rod photoresponse after

Stargardt macular degeneration and related retinal disorders

Stargardt disease is an early onset, autosomal recessive disease first described by the German ophthalmologist Karl Stargardt in 1909 [81]. It is the most common inherited macular dystrophy with a prevalence estimated to be 1 in 10,000 [82]. Characteristic features include significant loss in central vision in the first or second decade of life, progressive bilateral atrophy of the RPE and photoreceptors, yellow or white lipofuscin deposits within the macula at the level of the RPE cells

Model for the role of ABCA4 in the visual cycle and retinal degenerative diseases

Analyses of Stargardt patients together with biochemical characterization of ABCA4 and abca4 knockout mice have implicated ABCA4 in removal of retinoids from outer segments as part of the visual or retinoid cycle [55], [69], [70]. Following photoexcitation, all-trans retinal is released from rhodopsin and partitions into the lipid bilayer of disc membranes. Most of the all-trans retinal is reduced to all-trans retinol on the cytoplasmic side of the membrane by the retinol dehydrogenase RDH8 and

Therapeutic strategies for Stargardt macular degeneration and related diseases

Insight into the genetic and molecular basis for Stargardt and related ABCA4 retinal degenerative diseases has led to investigations into possible treatments for this set of disorders.

Gene therapy offers a promising approach to prevent or slow the onset of ABCA4 related diseases [114]. For recessive diseases, this typically involves the delivery of the normal gene to cells harboring the defective gene. This strategy has proven successful in animal models for a number of retinal degenerative

Conclusions

ABCA4 is an ABC transporter that is expressed in vertebrate rod and cone photoreceptors and localized to the rim regions of outer segment disc membranes. Mutations in ABCA4 are responsible for Stargardt macular degeneration and related retinal degenerative diseases that cause significant loss in vision. Functional properties of the purified protein together with biochemical analysis of abca4 knockout mice have implicated ABCA4 in the transport of N-retinylidene-PE across the disc membranes

Acknowledgements

This work was supported by grants from the Canadian Institutes of Health Research (MT 5822), National Eye Institute (EY02422) and a grant from the Macula Vision Research Foundation.

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