How to move an amphipathic molecule across a lipid bilayer: different mechanisms for different ABC transporters?

Frederica L Theodoulou,Alison Baker,David J Carrier,Stephen A Baldwin,Theresia A Schaedler

doi:10.1042/bst20160040

Abstract

Import of β-oxidation substrates into peroxisomes is mediated by ATP binding cassette (ABC) transporters belonging to subfamily D. In order to enter the β-oxidation pathway, fatty acids are activated by conversion to fatty acyl-CoA esters, a reaction which is catalysed by acyl-CoA synthetases (ACSs). Here, we present evidence for an unusual transport mechanism, in which fatty acyl-CoA substrates are accepted by ABC subclass D protein (ABCD) transporters, cleaved by the transporters during transit across the lipid bilayer to release CoA, and ultimately re-esterified in the peroxisome lumen by ACSs which interact with the transporter. We propose that this solves the biophysical problem of moving an amphipathic molecule across the peroxisomal membrane, since the intrinsic thioesterase activity of the transporter permits separate membrane translocation pathways for the hydrophobic fatty acid moiety and the polar CoA moiety. The cleavage/re-esterification mechanism also has the potential to control entry of disparate substrates into the β-oxidation pathway when coupled with distinct peroxisomal ACSs. A different solution to the movement of amphipathic molecules across a lipid bilayer is deployed by the bacterial lipid-linked oligosaccharide (LLO) flippase, PglK, in which the hydrophilic head group and the hydrophobic polyprenyl tail of the substrate are proposed to have distinct translocation pathways but are not chemically separated during transport. We discuss a speculative alternating access model for ABCD proteins based on the mammalian ABC transporter associated with antigen processing (TAP) and compare it to the novel mechanism suggested by the recent PglK crystal structures and biochemical data.

Highlights

A distinctive function of peroxisomes is the β-oxidation pathway in which fatty acids (FA) are degraded with the concomitant generation of acetyl-CoA [1]
The thioesterase activity of CTS may circumvent the requirement for a binding site which accommodates amphipathic molecules, since it allows for the possibility for the polar CoA moiety and the hydrophobic fatty acid moiety to take separate pathways through the peroxisomal membrane, i.e. fatty acids potentially interact with the transmembrane domains (TMDs) and/or flip-flop in the membrane whereas CoA may be transported through a hydrophilic channel in the TMDs or alternatively could be imported by another transporter, such as a member of the mitochondrial carrier family [49]
Whilst an alternating access/thioesterase model for asymmetric ATP binding cassette (ABC) transporters has many plausible features and is supported by experimental evidence for transporter associated with antigen processing (TAP), several questions arise when extending this model to CTS: (1) In the broad specificity Arabidopsis transporter, specific binding of the CoA moiety provides a potential explanation for how disparate CoA esters might be recognized

Summary

Introduction

A distinctive function of peroxisomes is the β-oxidation pathway in which fatty acids (FA) are degraded with the concomitant generation of acetyl-CoA [1]. Human ALDP and ALDR were targeted correctly to the peroxisome in plants, only ALDR was able to complement the germination phenotype of cts-1, consistent with the ability to import OPDA but neither transporter could restore seed oil mobilization or IBA metabolism, in line with their narrower substrate specificity [38] (Figure 1C).

Results

Conclusion