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

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 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.

A novel ABCD1 gene mutation causes adrenomyeloneuropathy presenting with spastic paraplegia: A case report

“…In addition, this mutation may also lead to breakdown of conformational states of ABCD1 protein. [12] Institutions in some places (e.g., New York State in the US) were allowed to conduct newborn screening for ALD disease prior to development of clinical manifestations and offer the opportunity for further genetic characterization and phenotyping, which showed the importance of identifying new gene mutation sites and corresponding phenotypes. [13,14] A novel hemizygous frameshift mutation c.249dupC (p.F83fs) in exon1 of the ABCD1 gene was identified in this case.…”

“…In addition, this mutation may also lead to breakdown of conformational states of ABCD1 protein. [12]…”

Identification of two novel heterodimeric ABC transporters in melanoma: ABCB5β/B6 and ABCB5β/B9

“…Janas and colleagues showed that purified NBD of Mdl1p, a homolog of the human ABC transporter TAP in S. cerevisiae , with an E559Q mutation, had residual ATP hydrolysis, though it was much lower than that of the WT protein ( 38 ). Similarly, the E630Q mutation in the human ABCD1 Walker B motif only resulted in a one third decrease of ATPase activity ( 39 ). In our case, only a 60% decrease is seen with the mutated transporters.…”