Homo- and Heterodimerization of Peroxisomal ATP-binding Cassette Half-transporters

• Published in: The Journal of biological chemistry 1999-11, Vol.274 (46), p.32738-32743
• Main Authors: Liu, Lang Xia, Janvier, Katy, Berteaux-Lecellier, Véronique, Cartier, Nathalie, Benarous, Richard, Aubourg, Patrick
• Format: Article
• Language: English
• Subjects: adrenoleukodystrophy; Adrenoleukodystrophy - etiology; Adrenoleukodystrophy - genetics; ALDP protein; ALDRP protein; Animals; ATP Binding Cassette Transporter, Subfamily D; ATP Binding Cassette Transporter, Subfamily D, Member 1; ATP-Binding Cassette Transporters - chemistry; ATP-Binding Cassette Transporters - genetics; Dimerization; Humans; Membrane Proteins - chemistry; Membrane Proteins - genetics; Mice; Mutagenesis; Peroxisomes - chemistry; PMP70 protein; Precipitin Tests; Protein Binding; Proteins - chemistry; Proteins - genetics; Yeasts
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.274.46.32738

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 β-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.