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Molecular structures of the eukaryotic retinal importer ABCA4.

<div class='caption-title'>Biochemical characterization of ABCA4.</div>
<div class='caption-title'>The overall structure of ABCA4 in the absence of ATP.</div>
<div class='caption-title'>Cryo-electron microscopy reconstructions of the ATP-free, wild-type ABCA4.</div>
Liu F, Lee J, Chen J
OpenAccess logo Elife 10 (2021)
Cited: 26 times
EuropePMC logo PMID: 33605212

Abstract

The ATP-binding cassette (ABC) transporter family contains thousands of members with diverse functions. Movement of the substrate, powered by ATP hydrolysis, can be outward (export) or inward (import). ABCA4 is a eukaryotic importer transporting retinal to the cytosol to enter the visual cycle. It also removes toxic retinoids from the disc lumen. Mutations in ABCA4 cause impaired vision or blindness. Despite decades of clinical, biochemical, and animal model studies, the molecular mechanism of ABCA4 is unknown. Here, we report the structures of human ABCA4 in two conformations. In the absence of ATP, ABCA4 adopts an outward-facing conformation, poised to recruit substrate. The presence of ATP induces large conformational changes that could lead to substrate release. These structures provide a molecular basis to understand many disease-causing mutations and a rational guide for new experiments to uncover how ABCA4 recruits, flips, and releases retinoids.

Reviews - 7lkp mentioned but not cited (2)

  1. Dynamic lipid turnover in photoreceptors and retinal pigment epithelium throughout life. Lewandowski D, Sander CL, Tworak A, Gao F, Xu Q, Skowronska-Krawczyk D. Prog Retin Eye Res 89 101037 (2022)
  2. Reconstitution of ATP-dependent lipid transporters: gaining insight into molecular characteristics, regulation, and mechanisms. Herrera SA, Günther Pomorski T. Biosci Rep 43 BSR20221268 (2023)

Articles - 7lkp mentioned but not cited (8)

  1. Cryo-EM structures of the ABCA4 importer reveal mechanisms underlying substrate binding and Stargardt disease. Scortecci JF, Molday LL, Curtis SB, Garces FA, Panwar P, Van Petegem F, Molday RS. Nat Commun 12 5902 (2021)
  2. Binding mode analysis of ABCA7 for the prediction of novel Alzheimer's disease therapeutics. Namasivayam V, Stefan K, Pahnke J, Stefan SM. Comput Struct Biotechnol J 19 6490-6504 (2021)
  3. Cholesterol efflux mechanism revealed by structural analysis of human ABCA1 conformational states. Sun Y, Li X. Nat Cardiovasc Res 1 238-245 (2022)
  4. Cryo-EM structures of human ABCA7 provide insights into its phospholipid translocation mechanisms. Le LTM, Thompson JR, Dehghani-Ghahnaviyeh S, Pant S, Dang PX, French JB, Kanikeyo T, Tajkhorshid E, Alam A. EMBO J 42 e111065 (2023)
  5. Strategies to gain novel Alzheimer's disease diagnostics and therapeutics using modulators of ABCA transporters. Pahnke J, Bascuñana P, Brackhan M, Stefan K, Namasivayam V, Koldamova R, Wu J, Möhle L, Stefan SM. Free Neuropathol 2 33 (2021)
  6. Protein modeling and in silico analysis to assess pathogenicity of ABCA4 variants in patients with inherited retinal disease. Cevik S, Wangtiraumnuay N, Van Schelvergem K, Tsukikawa M, Capasso J, Biswas SB, Bodt B, Levin AV, Biswas-Fiss E. Mol Vis 29 217-233 (2023)
  7. Stargardt disease-associated in-frame ABCA4 exon 17 skipping results in significant ABCA4 function. Kaltak M, Blanco-Garavito R, Molday LL, Dhaenens CM, Souied EE, Platenburg G, Swildens J, Molday RS, Cremers FPM. J Transl Med 21 546 (2023)
  8. The regulatory domains of the lipid exporter ABCA1 form domain swapped latches. Aller SG, Segrest JP. PLoS One 17 e0262746 (2022)


Reviews citing this publication (7)

  1. Phospholipid Scrambling by G Protein-Coupled Receptors. Khelashvili G, Menon AK. Annu Rev Biophys 51 39-61 (2022)
  2. An Overview of the Genetics of ABCA4 Retinopathies, an Evolving Story. Al-Khuzaei S, Broadgate S, Foster CR, Shah M, Yu J, Downes SM, Halford S. Genes (Basel) 12 1241 (2021)
  3. Biomedical Advances in ABCA1 Transporter: From Bench to Bedside. Choi HY, Choi S, Iatan I, Ruel I, Genest J. Biomedicines 11 561 (2023)
  4. Mass spectrometry-based retina proteomics. Prokai L, Zaman K, Prokai-Tatrai K. Mass Spectrom Rev 42 1032-1062 (2023)
  5. Phospholipid transport by ABCA1: the extracellular translocase or alternating access model? Segrest JP, Davidson WS, Heinecke JW. Curr Opin Lipidol 34 208-213 (2023)
  6. Structure and mechanism of the bacterial lipid ABC transporter, MlaFEDB. Ekiert DC, Coudray N, Bhabha G. Curr Opin Struct Biol 76 102429 (2022)
  7. The Scope of Pathogenic ABCA4 Mutations Targetable by CRISPR DNA Base Editing Systems-A Systematic Review. Piotter E, McClements ME, MacLaren RE. Front Genet 12 814131 (2021)

Articles citing this publication (9)

  1. Structure-Based Understanding of ABCA3 Variants. Onnée M, Fanen P, Callebaut I, de Becdelièvre A. Int J Mol Sci 22 10282 (2021)
  2. ABCA1 is an extracellular phospholipid translocase. Segrest JP, Tang C, Song HD, Jones MK, Davidson WS, Aller SG, Heinecke JW. Nat Commun 13 4812 (2022)
  3. Cryo-EM structures of the human surfactant lipid transporter ABCA3. Xie T, Zhang Z, Yue J, Fang Q, Gong X. Sci Adv 8 eabn3727 (2022)
  4. Determinants shaping the nanoscale architecture of the mouse rod outer segment. Pöge M, Mahamid J, Imanishi SS, Plitzko JM, Palczewski K, Baumeister W. Elife 10 e72817 (2021)
  5. Rare and common variants in ROM1 and PRPH2 genes trans-modify Stargardt/ABCA4 disease. Zernant J, Lee W, Wang J, Goetz K, Ullah E, Nagasaki T, Su PY, Fishman GA, Tsang SH, Tumminia SJ, Brooks BP, Hufnagel RB, Chen R, Allikmets R. PLoS Genet 18 e1010129 (2022)
  6. Retinal-phospholipid Schiff-base conjugates and their interaction with ABCA4, the ABC transporter associated with Stargardt disease. Xu T, Molday LL, Molday RS. J Biol Chem 299 104614 (2023)
  7. Structural and Pathogenic Impacts of ABCA4 Variants in Retinal Degenerations-An In-Silico Study. Cevik S, Biswas SB, Biswas-Fiss EE. Int J Mol Sci 24 7280 (2023)
  8. Structural basis for abscisic acid efflux mediated by ABCG25 in Arabidopsis thaliana. Ying W, Liao L, Wei H, Gao Y, Liu X, Sun L. Nat Plants 9 1697-1708 (2023)
  9. Structural basis of substrate recognition and translocation by human ABCA4. Xie T, Zhang Z, Fang Q, Du B, Gong X. Nat Commun 12 3853 (2021)


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