ATP-binding cassette (ABC) transporters are members of a superfamily of membrane proteins involved in the transport of a variety of molecules across biological membranes. In eukaryotes, they are found either as complete transporters (e.g., the multidrug resistance [MDR1] and the cystic fibrosis transmembrane conductance regulator [CFTR] proteins) or as a half transporters which require dimerization to become functional (e.g., TAP1/TAP2 in the membrane of the endoplasmic reticulum).

At least three half ABC transporters have been identified in the human peroxisome membrane: the adrenoleukodystrophy protein (ALDP); the 70-kDa peroxisomal membrane protein (PMP70); and an ALDP-related protein (ALDR). ALDP mutations cause X-linked adrenoleukodystrophy and PMP70 mutations have been implicated as one cause of the Zellweger syndrome.

Based on results in the yeast homologs, we predict similar heterodimeric interactions of the mammalian peroxisomal membrane half ABC transporters and are currently utilizing homologous recombination to explore the role of PMP70 in this model. We have successfully targeted the PMP70 gene in ES cells, produced chimera mice and are in the process of producing heterozygous mice. We also targeted PMP70 in myoblasts and plan to produce cellular and whole animal models lacking PMP70.

We will examine the consequences of deficiency of PMP70 on peroxisomal structure and function and on the stability and function of the other mammalian peroxisomal half ABC transporters.