Substrate Specificity and the Direction of Transport in the ABC Transporters ABCD1-3 and ABCD4.

The ATP-binding cassette (ABC) transporters are one of the largest families of membrane-bound proteins and exist in almost all living organisms from eubacteria to mammals. They transport diverse substrates across membranes utilizing the energy of ATP hydrolysis as a driving force and play an essential role in cellular homeostasis. In humans, four ABC transporters classified as subfamily D have been identified. ABCD1-3 are localized to peroxisomal membranes and involved in the transport of various acyl-CoAs from the cytosol to the peroxisomal lumen. ABCD4 functions on the lysosomal membranes and transports vitamin B12 (cobalamin) from lysosomes into the cytosol. The mutation of genes encoding ABCD1, ABCD3, and ABCD4 are responsible for genetic diseases called X-linked adrenoleukodystrophy, congenital bile acid synthesis defect 5, and cobalamin deficiency, respectively. In this review, we summarize the targeting mechanism and physiological functions of the ABCD transporters and discuss insights that have been obtained on the transport mechanism based on disease-causing mutations and cryo-electron microscopy (EM) structural studies.