Structures of the human peroxisomal fatty acid transporter ABCD1 in a lipid environment

Abstract

The peroxisomal very long chain fatty acid (VLCFA) transporter ABCD1 is central to cellular fatty acid catabolism and lipid biosynthesis. Its dysfunction underlies toxic cytosolic accumulation of VLCFAs, progressive nervous system demyelination, and neurological impairments including the potentially fatal disease X-linked adrenoleukodystrophy (X-ALD). Molecular details underlying substrate recognition and transport by ABCD1 are poorly understood. Here we determined cryo-EM structures of ABCD1 in phospholipid nanodiscs in a nucleotide bound conformation open to the peroxisomal lumen and an inward facing conformation open to the cytosol at up to 3.5 [A] resolution that reveal key details of its transmembrane cavity and ATP dependent conformational transitions. We identify structural elements distinguishing ABCD1 from its closest homologs and show that coenzyme A (CoA) esters of VLCFAs modulate ABCD1 activity in a species dependent manner. Together, our data support a transport mechanism where only the CoA moieties of VLCFA-CoAs enter the hydrophilic transmembrane cavity while the acyl chains extend out into the surrounding membrane bilayer, help rationalize disease causing mutations, and provide a framework for ABCD1 targeted structure-based drug design.