Predictive Structure and Topology of Peroxisomal ATP-Binding Cassette (ABC) Transporters.

Pierre Andreoletti,Mustapha Cherkaoui-Malki,Catherine Gondcaille,Doriane Trompier,Quentin Raas,Stéphane Savary

doi:10.3390/ijms18071593

Pierre Andreoletti, Mustapha Cherkaoui-Malki + Show 4 more

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https://doi.org/10.3390/ijms18071593

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Abstract

The peroxisomal ATP-binding Cassette (ABC) transporters, which are called ABCD1, ABCD2 and ABCD3, are transmembrane proteins involved in the transport of various lipids that allow their degradation inside the organelle. Defective ABCD1 leads to the accumulation of very long-chain fatty acids and is associated with a complex and severe neurodegenerative disorder called X-linked adrenoleukodystrophy (X-ALD). Although the nucleotide-binding domain is highly conserved and characterized within the ABC transporters family, solid data are missing for the transmembrane domain (TMD) of ABCD proteins. The lack of a clear consensus on the secondary and tertiary structure of the TMDs weakens any structure-function hypothesis based on the very diverse ABCD1 mutations found in X-ALD patients. Therefore, we first reinvestigated thoroughly the structure-function data available and performed refined alignments of ABCD protein sequences. Based on the 2.85 Å resolution crystal structure of the mitochondrial ABC transporter ABCB10, here we propose a structural model of peroxisomal ABCD proteins that specifies the position of the transmembrane and coupling helices, and highlight functional motifs and putative important amino acid residues.

Highlights

ATP-Binding Cassette (ABC) transporters belong to a superfamily conserved from bacteria to humans [1]
Homodimers and heterodimers of half-transporters coexist with full-length ABC transporters, i.e., proteins composed of the four domains covalently linked (TMD-nucleotide-binding domains (NBDs)-transmembrane domain (TMD)-NBD) such as ABCB1 (P-glycoprotein), which is associated with multidrug resistance
Using refined alignments of ABCD protein sequences and homology modeling based on the 2.85 Å resolution crystal structure of mitochondrial ABC transporter ABCB10, we propose a structural model of ABCD1 which specifies the position of the transmembrane and coupling helices, and highlights new functional putative motifs of the TMD

Summary

Introduction

ATP-Binding Cassette (ABC) transporters belong to a superfamily conserved from bacteria to humans [1]. With the exception of a few members, ABC transporters are transmembrane proteins whose minimal functional unit is predicted to contain two nucleotide-binding domains (NBDs) and two transmembrane domains (TMDs) [2]. Each domain can result from the expression of independent genes and bind together post-translationally to form a functional ABC transporter as in the case of the E. coli nickel transporter [3]. Homodimers (for instance ABCG2, a transporter involved in multidrug resistance) and heterodimers (for instance ABCB2/ABCB3—Tap1/Tap, the transporter associated with antigen presentation) of half-transporters coexist with full-length ABC transporters, i.e., proteins composed of the four domains covalently linked (TMD-NBD-TMD-NBD) such as ABCB1 (P-glycoprotein), which is associated with multidrug resistance. The sequence of the NBDs is very well conserved among the superfamily, in particular for the Walker A and B motifs and the ABC transporter signature (ATS) motifs which are all required for binding and hydrolysis of ATP. These interactions result in the tight coupling between substrate transport and ATP hydrolysis

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