title: Homo- and heterodimerization of peroxisomal ATP-binding cassette half-transporters.
abstract: Mammalian peroxisomal proteins adrenoleukodystrophy protein (ALDP), adrenoleukodystrophy-related protein (ALDRP), and 70-kDa peroxisomal protein (PMP70) belong to the superfamily of ATP-binding cassette (ABC) transporters. Unlike many ABC transporters that are single functional proteins with two related halves, ALDP, ALDRP, and PMP70 have the structure of ABC half-transporters. The dysfunction of ALDP is responsible for X-linked adrenoleukodystrophy (X-ALD), a neurodegenerative disorder in which saturated very long-chain fatty acids accumulate because of their impaired peroxisomal beta-oxidation. No disease has so far been associated with mutations of adrenoleukodystrophy-related or PMP70 genes. It has been proposed that peroxisomal ABC transporters need to dimerize to exert import functions. Using the yeast two-hybrid system, we show that homo- as well as heterodimerization occur between the carboxyl-terminal halves of ALDP, ALDRP, and PMP70. Two X-ALD disease mutations located in the carboxyl-terminal half of ALDP affect both homo- and heterodimerization of ALDP. Co-immunoprecipitation demonstrated the homodimerization of ALDP, the heterodimerization of ALDP with PMP70 or ALDRP, and the heterodimerization of ALDRP with PMP70. These results provide the first evidence of both homo- and heterodimerization of mammalian ABC half-transporters and suggest that the loss of ALDP dimerization plays a role in X-ALD pathogenesis.
authors.affiliation: INSERM U342, Institut Cochin de Génétique Moléculaire, Hôpital Saint-Vincent-de-Paul, 82 Avenue Denfert Rochereau, 75014 Paris, France.
authors.forename: L X
authors.initials: LX
authors.lastname: Liu
authors.forename: K
authors.initials: K
authors.lastname: Janvier
authors.forename: V
authors.initials: V
authors.lastname: Berteaux-Lecellier
authors.forename: N
authors.initials: N
authors.lastname: Cartier
authors.forename: R
authors.initials: R
authors.lastname: Benarous
authors.forename: P
authors.initials: P
authors.lastname: Aubourg
mesh_terms: D000074061:ATP Binding Cassette Transporter, Subfamily D; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters / Q000737:chemistry* / Q000235:genetics; D000326:Adrenoleukodystrophy / Q000209:etiology / Q000235:genetics; D000818:Animals; D019281:Dimerization; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics; D051379:Mice; D016296:Mutagenesis; D020675:Peroxisomes / Q000737:chemistry*; D011233:Precipitin Tests; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry* / Q000235:genetics; D015003:Yeasts
chemical_list: C115572:ABCD1 protein, human; C431694:ABCD2 protein, human; C063305:ABCD3 protein, human; D000074061:ATP Binding Cassette Transporter, Subfamily D; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters; C489271:Abcd3 protein, mouse; D008565:Membrane Proteins; D011506:Proteins