3.A.1.211.2
The retinal-specific ABC transporter (RIM protein, ABCR or ABCA4) (Stargardt's disease protein, involved in retinal/macular degeneration) in the rod outer segment (Garces et al. 2020). Changes in the oligomeric state of the nucleotide binding domains of ABCR are coupled to ATP hydrolysis and might represent a signal for the TMDs of ABCR to export the bound substrate (Biswas-Fiss 2006). The ABCA4 porter flips N-retinylidene-phosphatidylethanolamine, a product generated from the photobleaching of rhodopsin, from the lumen to the cytoplasmic side of disc membranes following the photobleaching of rhodopsin, insuring that retinoids do not accumulate in disc membranes (Molday, 2007; Molday et al. 2009; Tsybovsky et al. 2013). It also transports several vitamin A derivatives (Sun, 2011) and phosphatidylethanolamine in the same direction. Mutations, known to cause Stargardt disease, decrease N-retinylidene-phosphatidylethanolamine and phosphatidylethanolamine transport activities (Quazi et al. 2012). It functions as an inwardly directed retinoid flippase in the visual cycle (Sakamoto et al. 2019). Three cryo-EM structures of human ABCA4, a retina-specific ABCA transporter, in distinct functional states have been solved at resolutions of 3.3-3.4 Å (Xie et al. 2021). 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 substrate binding (Xie et al. 2021). ABCA4 flips N-retinylidene phosphatidylethanolamine (N-Ret-PE) from the lumen to the cytoplasmic leaflet of photoreceptor membranes. Loss-of-function mutations cause Stargardt disease (STGD1), a macular dystrophy associated with severe vision loss. Scortecci et al. 2021 determined the cryo-EM structure of ABCA4 in its substrate-free and bound states. The two structures are similar and delineate an elongated protein with the two TMSs forming an outward facing conformation, extended and twisted exocytoplasmic domains (ECD), and closely opposed nucleotide binding domains. N-Ret-PE is wedged between the two TMSs and a loop from ECD1 within the lumenal leaflet, consistent with a lateral access mechanism. It is stabilized through hydrophobic and ionic interactions with residues from the TMSs and ECDs (Scortecci et al. 2021). ABCA4 retinopathy-associated variants may be associated with retinal structure and subclinical disease (Simcoe et al. 2023). Stargardt disease-associated in-frame ABCA4 exon 17 skipping results in significant ABCA4 function (Kaltak et al. 2023). Inherited macular dystrophies (iMDs) are a group of genetic disorders, which affect the central region of the retina. The top most frequent causative gene was ABCA4 (37.2%) (Hitti-Malin et al. 2024). Hereditary retinal disease is often caused by defects in ABCA4 (Ozguc Caliskan et al. 2024). ABCA4-associated retinal degeneration is caused by disease-causing variants in ABCA4 (Chacon-Camacho et al. 2024). ABCA4 prevents the buildup of toxic retinoid compounds by facilitating the transport of N-retinylidene-phosphatidylethanolamine across membranes of rod and cone photoreceptor cells (Scortecci et al. 2024).