7e7i | pdb_00007e7i
Cryo-EM structure of human ABCA4 in the apo state
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 PubMedHuman ATP-binding cassette (ABC) subfamily A (ABCA) transporters mediate the transport of various lipid compounds across the membrane. Mutations in human ABCA transporters have been described to cause severe hereditary disorders associated with impaired lipid transport. However, little is known about the mechanistic details of substrate recognition and translocation by ABCA transporters. Here, we present three cryo-EM structures of human ABCA4, a retina-specific ABCA transporter, in distinct functional states at resolutions of 3.3-3.4 A. In the nucleotide-free state, the two transmembrane domains (TMDs) exhibit a lateral-opening conformation, allowing the lateral entry of substrate from the lipid bilayer. The N-retinylidene-phosphatidylethanolamine (NRPE), the physiological lipid substrate of ABCA4, is sandwiched between the two TMDs in the luminal leaflet and is further stabilized by an extended loop from extracellular domain 1. In the ATP-bound state, the two TMDs display a closed conformation, which precludes the substrate binding. Our study provides a molecular basis to understand the mechanism of ABCA4-mediated NRPE recognition and translocation, and suggests a common 'lateral access and extrusion' mechanism for ABCA-mediated lipid transport. Structural basis of substrate recognition and translocation by human ABCA4.,Xie T, Zhang Z, Fang Q, Du B, Gong X Nat Commun. 2021 Jun 22;12(1):3853. doi: 10.1038/s41467-021-24194-6. PMID:34158497[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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