A novel missense mutation in the ABCD1 gene of a Chinese boy diagnosed with X-linked adrenoleukodystrophy: case report

et al. 2021

Preprint

The malfunction of ABCD1 causes X-linked adrenoleukodystrophy (X-ALD), a rare neurodegenerative disease that affect all tissues in human. Residing in the peroxisome membrane, ABCD1 plays a role in the translocation of very long chain fatty acids (VLCFA) for their damage by β-oxidation. Here, we present five Cryo-Electron microscopy structures of ABCD1 in four conformational states. Combined with functional analysis, we found that substrate and ATP trigger the closing of two nucleotide binding domains (NBDs) over a distance of 40 Å and the rearrangement of the transmembrane domains. Each of the three inward-facing structure of ABCD1 has a vestibule opens to cytosol with variable size. Furthermore, the structure of ABCD1 in the outward-facing state supports that ATP molecules pull the two NBDs together and open the transmembrane domain to the peroxisomal lumen for substrate release. The five structures provide a snapshot of substrate transporting cycle and mechanistic implications for disease-causing mutations.

Section: Discussionmentioning

confidence: 99%

ATP and Substrate Binding Regulates Conformational Changes of Human Peroxisomal ABC Transporter ALDP

Tang

et al. 2021

Preprint

“…6e), and its mutation to proline may affect the correct orientation of the coiled-coil helix, decoupling its interaction with the Walker A motif of the NBDs. Furthermore, mutations to various residues have been reported on positions W339 and R401, 32,[37][38][39][40] which were situated at the substrate-binding site (Fig. 6d).…”

Section: Conformational Changes During the Translocation Process Of A...mentioning

confidence: 96%

Structural insights into substrate recognition and translocation of human peroxisomal ABC transporter ALDP

Sig Transduct Target Ther

Xiong

et al. 2023

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.

“…On the other hand, L684 positioned at the very beginning of the C-terminal coiled-coil (Figure 7E), its mutation to proline may affect the correct orientation of the coiled-coil helix, decoupling its interaction with the Walker A motif of the NBDs. Furthermore, mutations to a variety of residues have been reported on positions of W339 and R401 (Chu et al, 2015;Coll et al, 2005;Kumar et al, 2011;Wichers et al, 1999;Zhang et al, 2019), which situates at the substrate binding site (Figure 7D). In addition, a large number of interaction appears at the outward facing conformation of ABCD1.…”

Section: Structural Basis Of Disease-causing Mutationsmentioning

confidence: 99%

ATP and Substrate Binding Regulates Conformational Changes of Human Peroxisomal ABC Transporter ALDP

Shen

et al. 2021

Preprint

The malfunction of ABCD1 causes X-linked adrenoleukodystrophy (X-ALD), a rare neurodegenerative disease that affect all tissues in human. Residing in the peroxisome membrane, ABCD1 plays a role in the translocation of very long chain fatty acids (VLCFA) for their damage by β-oxidation. Here, we present five Cryo-Electron microscopy structures of ABCD1 in four conformational states. Combined with functional analysis, we found that substrate and ATP trigger the closing of two nucleotide binding domains (NBDs) over a distance of 40 &Aring and the rearrangement of the transmembrane domains. Each of the three inward-facing structure of ABCD1 has a vestibule opens to cytosol with variable size. Furthermore, the structure of ABCD1 in the outward-facing state supports that ATP molecules pull the two NBDs together and open the transmembrane domain to the peroxisomal lumen for substrate release. The five structures provide a snapshot of substrate transporting cycle and mechanistic implications for disease-causing mutations.