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-Structure paper
Title | Structural insights into substrate recognition and translocation of human peroxisomal ABC transporter ALDP. |
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Journal, issue, pages | Signal Transduct Target Ther, Vol. 8, Issue 1, Page 74, Year 2023 |
Publish date | Feb 22, 2023 |
Authors | Chao Xiong / Li-Na Jia / Wei-Xi Xiong / Xin-Tong Wu / Liu-Lin Xiong / Ting-Hua Wang / Dong Zhou / Zhen Hong / Zheng Liu / Lin Tang / |
PubMed Abstract | Dysfunctions 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 ...Dysfunctions 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 β-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. |
External links | Signal Transduct Target Ther / PubMed:36810450 / PubMed Central |
Methods | EM (single particle) |
Resolution | 2.96 - 3.78 Å |
Structure data | EMDB-32919, PDB-7x07: EMDB-32924, PDB-7x0t: EMDB-32930, PDB-7x0z: EMDB-32951, PDB-7x1w: EMDB-33155, PDB-7xec: EMDB-34064, PDB-7yrq: |
Chemicals | ChemComp-7PO: ChemComp-CO8: ChemComp-ATP: ChemComp-MG: ChemComp-K9G: |
Source |
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Keywords | STRUCTURAL PROTEIN / complex / Membrane protein / ligand |