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==Structure of ATP-free human ABCA4== | ==Structure of ATP-free human ABCA4== | ||
<StructureSection load='7lkp' size='340' side='right'caption='[[7lkp]]' scene=''> | <StructureSection load='7lkp' size='340' side='right'caption='[[7lkp]], [[Resolution|resolution]] 3.27Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7LKP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LKP FirstGlance]. <br> | <table><tr><td colspan='2'>[[7lkp]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7LKP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LKP FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7lkp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lkp OCA], [https://pdbe.org/7lkp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lkp RCSB], [https://www.ebi.ac.uk/pdbsum/7lkp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lkp ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AJP:Digitonin'>AJP</scene>, <scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=POV:(2S)-3-(HEXADECANOYLOXY)-2-[(9Z)-OCTADEC-9-ENOYLOXY]PROPYL+2-(TRIMETHYLAMMONIO)ETHYL+PHOSPHATE'>POV</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ABCA4, ABCR ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/P-type_phospholipid_transporter P-type phospholipid transporter], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=7.6.2.1 7.6.2.1] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7lkp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lkp OCA], [https://pdbe.org/7lkp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lkp RCSB], [https://www.ebi.ac.uk/pdbsum/7lkp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lkp ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Disease == | |||
[[https://www.uniprot.org/uniprot/ABCA4_HUMAN ABCA4_HUMAN]] Cone rod dystrophy;NON RARE IN EUROPE: Age-related macular degeneration;Stargardt disease;Retinitis pigmentosa. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. Disease susceptibility is associated with variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. | |||
== Function == | |||
[[https://www.uniprot.org/uniprot/ABCA4_HUMAN ABCA4_HUMAN]] Catalyzes the translocation of specific phospholipids from the extracellular/lumenal to the cytoplasmic leaflet of membrane coupled to the hydrolysis of ATP (PubMed:24097981). Transports preferentially phosphatidylethanolamine (PubMed:24097981). In the visual cycle, acts as an inward-directed retinoid flipase, retinoid substrates imported by ABCA4 from the extracellular or intradiscal (rod) membrane surfaces to the cytoplasmic membrane surface are all-trans-retinaldehyde (ATR) and N-retinyl-phosphatidyl-ethanolamine (NR-PE). Once transported to the cytoplasmic surface, ATR is reduced to vitamin A by trans-retinol dehydrogenase (tRDH) and then transferred to the retinal pigment epithelium (RPE) where it is converted to 11-cis-retinal. May play a role in photoresponse, removing ATR/NR-PE from the extracellular photoreceptor surfaces during bleach recovery.<ref>PMID:10075733</ref> <ref>PMID:24097981</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
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 to the cytosol. 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. | |||
Molecular structures of the eukaryotic retinal importer ABCA4.,Liu F, Lee J, Chen J Elife. 2021 Feb 19;10. pii: 63524. doi: 10.7554/eLife.63524. PMID:33605212<ref>PMID:33605212</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7lkp" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[ATPase 3D structures|ATPase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Chen J]] | [[Category: P-type phospholipid transporter]] | ||
[[Category: Lee J]] | [[Category: Chen, J]] | ||
[[Category: Liu F]] | [[Category: Lee, J]] | ||
[[Category: Liu, F]] | |||
[[Category: Abc transporter]] | |||
[[Category: Importer]] | |||
[[Category: Membrane protein]] | |||
[[Category: Translocase]] | |||
Revision as of 09:33, 25 August 2021
Structure of ATP-free human ABCA4Structure of ATP-free human ABCA4
Structural highlights
Disease[ABCA4_HUMAN] Cone rod dystrophy;NON RARE IN EUROPE: Age-related macular degeneration;Stargardt disease;Retinitis pigmentosa. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. Disease susceptibility is associated with variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. Function[ABCA4_HUMAN] Catalyzes the translocation of specific phospholipids from the extracellular/lumenal to the cytoplasmic leaflet of membrane coupled to the hydrolysis of ATP (PubMed:24097981). Transports preferentially phosphatidylethanolamine (PubMed:24097981). In the visual cycle, acts as an inward-directed retinoid flipase, retinoid substrates imported by ABCA4 from the extracellular or intradiscal (rod) membrane surfaces to the cytoplasmic membrane surface are all-trans-retinaldehyde (ATR) and N-retinyl-phosphatidyl-ethanolamine (NR-PE). Once transported to the cytoplasmic surface, ATR is reduced to vitamin A by trans-retinol dehydrogenase (tRDH) and then transferred to the retinal pigment epithelium (RPE) where it is converted to 11-cis-retinal. May play a role in photoresponse, removing ATR/NR-PE from the extracellular photoreceptor surfaces during bleach recovery.[1] [2] Publication Abstract from PubMedThe 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 to the cytosol. 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. Molecular structures of the eukaryotic retinal importer ABCA4.,Liu F, Lee J, Chen J Elife. 2021 Feb 19;10. pii: 63524. doi: 10.7554/eLife.63524. PMID:33605212[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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