7x0t
Cryo-EM structure of human ABCD1 E630Q in the presence of C26:0-CoA and ATP
Structural highlights
DiseaseABCD1_HUMAN X-linked cerebral adrenoleukodystrophy;Adrenomyeloneuropathy;CADDS. The disease is caused by variants affecting the gene represented in this entry. The promoter region of ABCD1 is deleted in the chromosome Xq28 deletion syndrome which involves ABCD1 and the neighboring gene BCAP31.[1] FunctionABCD1_HUMAN ATP-dependent transporter of the ATP-binding cassette (ABC) family involved in the transport of very long chain fatty acid (VLCFA)-CoA from the cytosol to the peroxisome lumen (PubMed:11248239, PubMed:15682271, PubMed:16946495, PubMed:18757502, PubMed:21145416, PubMed:23671276, PubMed:29397936, PubMed:33500543). Coupled to the ATP-dependent transporter activity has also a fatty acyl-CoA thioesterase activity (ACOT) and hydrolyzes VLCFA-CoA into VLCFA prior their ATP-dependent transport into peroxisomes, the ACOT activity is essential during this transport process (PubMed:33500543, PubMed:29397936). Thus, plays a role in regulation of VLCFAs and energy metabolism namely, in the degradation and biosynthesis of fatty acids by beta-oxidation, mitochondrial function and microsomal fatty acid elongation (PubMed:23671276, PubMed:21145416). Involved in several processes; namely, controls the active myelination phase by negatively regulating the microsomal fatty acid elongation activity and may also play a role in axon and myelin maintenance. Controls also the cellular response to oxidative stress by regulating mitochondrial functions such as mitochondrial oxidative phosphorylation and depolarization. And finally controls the inflammatory response by positively regulating peroxisomal beta-oxidation of VLCFAs (By similarity).[UniProtKB:P48410][2] [3] [4] [5] [6] [7] [8] [9] Publication Abstract from PubMedDysfunctions of ATP-binding cassette, subfamily D, member 1 (ABCD1) cause X-linked adrenoleukodystrophy, a rare neurodegenerative disease that affects all human tissues. Residing in the peroxisome membrane, ABCD1 plays a role in the translocation of very long-chain fatty acids for their beta-oxidation. Here, the six cryo-electron microscopy structures of ABCD1 in four distinct conformational states were presented. In the transporter dimer, two transmembrane domains form the substrate translocation pathway, and two nucleotide-binding domains form the ATP-binding site that binds and hydrolyzes ATP. The ABCD1 structures provide a starting point for elucidating the substrate recognition and translocation mechanism of ABCD1. Each of the four inward-facing structures of ABCD1 has a vestibule that opens to the cytosol with variable sizes. Hexacosanoic acid (C26:0)-CoA substrate binds to the transmembrane domains (TMDs) and stimulates the ATPase activity of the nucleotide-binding domains (NBDs). W339 from the transmembrane helix 5 (TM5) is essential for binding substrate and stimulating ATP hydrolysis by substrate. ABCD1 has a unique C-terminal coiled-coil domain that negatively modulates the ATPase activity of the NBDs. Furthermore, the structure of ABCD1 in the outward-facing state indicates that ATP molecules pull the two NBDs together and open the TMDs to the peroxisomal lumen for substrate release. The five structures provide a view of the substrate transport cycle and mechanistic implication for disease-causing mutations. Structural insights into substrate recognition and translocation of human peroxisomal ABC transporter ALDP.,Xiong C, Jia LN, Xiong WX, Wu XT, Xiong LL, Wang TH, Zhou D, Hong Z, Liu Z, Tang L Signal Transduct Target Ther. 2023 Feb 22;8(1):74. doi: , 10.1038/s41392-022-01280-9. PMID:36810450[10] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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