The 70-kDa peroxisomal membrane protein (PMP70) and the adrenoleukodystrophy protein (ALDP aka ABCD1) are half ATP binding cassette (ABC) transporters in the peroxisome membrane. They are involved in metabolic transport of long and very long chain fatty acids into peroxisomes. Mutations in the ALD gene result in the X-linked neurodegenerative disorder adrenoleukodystrophy (ALD; MIM:300100). ABCD1 deficiency impairs the peroxisomal beta-oxidation of very long-chain fatty acids (VLCFA) and facilitates their further chain elongation by ELOVL1 resulting in accumulation of VLCFA in plasma and tissues. While all patients with ALD have mutations in the ABCD1 gene, there is no general genotype-phenotype correlation. In addition to ABCD1, other genes and environmental factors determine clinical features of ALD (Kemp et al. 2012, Berger et al. 2014).

The 70-kDa peroxisomal membrane protein (PMP70) and the adrenoleukodystrophy protein (ALDP aka ABCD1) are half ATP binding cassette (ABC) transporters in the peroxisome membrane. They are involved in metabolic transport of long and very long chain fatty acids into peroxisomes. Mutations in the ALD gene result in the X-linked neurodegenerative disorder adrenoleukodystrophy (ALD; MIM:300100). ABCD1 deficiency impairs the peroxisomal beta-oxidation of very long-chain fatty acids (VLCFA) and facilitates their further chain elongation by ELOVL1 resulting in accumulation of VLCFA in plasma and tissues. While all patients with ALD have mutations in the ABCD1 gene, there is no general genotype-phenotype correlation. Mutations causing ALD include R617C, S606L, M1V, G277R, R554H and W77_L82del (Krasemann et al. 1996, Fanen et al. 1994, Engelen et al. 2011, Coll et al. 2005, Park et al. 2014).

The 70-kDa peroxisomal membrane protein (PMP70) and the adrenoleukodystrophy protein (ALDP aka ABCD1) are half ATP binding cassette (ABC) transporters in the peroxisome membrane. They are involved in metabolic transport of long and very long chain fatty acids into peroxisomes. Mutations in the ALD gene result in the X-linked neurodegenerative disorder adrenoleukodystrophy (ALD; MIM:300100). ABCD1 deficiency impairs the peroxisomal beta-oxidation of very long-chain fatty acids (VLCFA) and facilitates their further chain elongation by ELOVL1 resulting in accumulation of VLCFA in plasma and tissues. While all patients with ALD have mutations in the ABCD1 gene, there is no general genotype-phenotype correlation. In addition to ABCD1, other genes and environmental factors determine clinical features of ALD (Kemp et al. 2012, Berger et al. 2014).

PEX19 is a chaperone protein that binds a broad spectrum of peroxisomal membrane proteins (PMPs), and interacts with regions of PMPs required for their targeting to peroxisomes. PEX3 is required for PEX19 to dock at peroxisomes, interacts specifically with the docking domain of PEX19, and is required for recruitment of the PEX19 docking domain to peroxisomes. The ABC transporters D1, D2 and D3 must first form dimers to become fully functional (Liu et al.1999) which then can bind with PEX19.

Homodimeric ABCD1 associated with the peroxisomal membrane mediates the uptake of cytosolic very long chain fatty acyl CoAs such as hexacosanoyl-CoA into the peroxisomal matrix. While the requirement for this uptake step in the catabolism of very long chain fatty acids is well-established, direct evidence for the function of ABCD1 as a transporter comes only from studies of its ability to restore peroxisomal long chain fatty acid catabolism in yeast strains whose endogenous transporters have been disrupted by mutation. ABCD1 is inferred to function as a dimer like other members of the ABCD transporter family. The energy requirements of peroxisomal fatty acid uptake (other ABCD transporter-mediated reactions are coupled to ATP hydrolysis) have not been established (van Roermund et al. 2008).

In the cytosol, PEX19 binds newly synthesized class I peroxisomal membrane proteins (Sacksteder et al. 2000, Fransen et al. 2001, Jones et al. 2004, reviewed in Fujiki et al. 2006). The C-terminal region and a conserved N-terminal helical segment of PEX19 bind to peroxisomal membrane proteins (Fransen et al. 2005, Schueller et al. 2010) and PEX19 acts both as a chaperone and as an import receptor (Jones et al. 2004). PEX19 is farnesylated (Götte et al. 1998, Sacksteder et al. 2000, Vastiau et al. 2006) and the farnesyl group is buried in a hydrophobic cavity which alters the conformation of PEX19 to yield two hydrophobic pockets involved in binding peroxisomal membrane proteins (Emmanouilidis et al. 2017). The number of positively charged amino acid residues in the transmembrane domain of the PMP appears to determine binding by PEX19 and, hence, targeting to the peroxisomal membrane protein (Costello et al. 2017).
Class I membrane proteins are inserted into the peroxisomal membrane after peroxisomal progenitors have budded from the endoplasmic reticulum (Jones et al. 2004). Human class I peroxisomal membrane proteins that are bound by PEX19 include PEX10 (Sacksteder et al. 2000), PEX11B (Fransen et al. 2005), PEX12 (Sacksteder et al. 2000, Fransen et al. 2001, Fransen et al. 2005), PEX13 (Sacksteder et al. 2000, Fransen et al. 2001, Fransen et al. 2005, Vastiau et al. 2006, Liu et al. 2016), PEX14 (Sacksteder et al. 2000, Fransen et al. 2005, Vastiau et al. 2006), PEX16 (Fransen et al. 2001, Fransen et al. 2005, Matsuzono and Fujiki 2006, Schueller et al. 2010, Yagita et al. 2013, Liu et al. 2016), ), PEX26 (Fransen et al. 2005, Matsuzono and Fujiki 2006), ABCD1 (ALDP, Mayerhofer et al. 2002, Halbach et al. 2005), ABCD2 (ALDRP, Mayerhofer et al. 2002), ABCD3 (PMP70, Sacksteder et al. 2000, Mayerhofer et al. 2002), PXMP2 (PMP22, Jones et al. 2001, Brosius et al. 2002), PXMP4 (PMP24, Pinto et al. 2006), SLC25A17 (PMP34, Sacksteder et al. 2000, Liu et al. 2016), ATAD1 (Liu et al. 2016), FIS1 (Delille and Schrader 2008), and GDAP1 (Huber et al. 2013).

ATP-binding cassette sub-family D member 1