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

2016 ◽  
Vol 44 (3) ◽  
pp. 774-782 ◽  
Author(s):  
Frederica L. Theodoulou ◽  
David J. Carrier ◽  
Theresia A. Schaedler ◽  
Stephen A. Baldwin ◽  
Alison Baker
Keyword(s):  
Lipid Bilayer ◽  
Abc Transporters ◽  
Antigen Processing ◽  
Fatty Acyl ◽  
Head Group ◽  
The Novel ◽  
Peroxisomal Membrane ◽  
Oxidation Pathway ◽  
Oxidation Substrates ◽  
Bacterial Lipid

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.

scholarly journals Structure insights of the human peroxisomal ABC transporter ALDP

2021 ◽  
Author(s):  
Yutian Jia ◽  
Yanming Zhang ◽  
Jianlin Lei ◽  
Guanghui Yang
Keyword(s):  
Structural Information ◽  
Free State ◽  
Head Group ◽  
Working Mechanism ◽  
Peroxisomal Membrane ◽  
Binding Domains ◽  
Cryo Electron Microscopy ◽  
Ligand Free ◽  
Clinical Description

Adrenoleukodystrophy protein (ALDP) is responsible for the transport of free very-long-chain fatty acids (VLCFAs) and corresponding CoA-esters across the peroxisomal membrane. ALDP belongs to the ATP-binding cassette sub-family D, which is also named as ABCD1. Dysfunction of ALDP leads to peroxisomal metabolic disorder exemplified by X-linked adrenoleukodystrophy (ALD). Hundreds of ALD-causing mutations are identified on ALDP. However, the pathogenic mechanisms of these mutations are restricted to clinical description due to limited structural information. Furthermore, ALDP plays a role in myelin maintenance, which is tightly associated with axon regeneration. Here we report the cryo-electron microscopy (cryo-EM) structure of human ALDP with nominal resolution of 3.4 angstrom in nucleotide free state. The structure of ALDP exhibits a typical assembly of ABC transporters. The nucleotide binding domains (NBDs) displays a ligand free state. ALDP exhibits an inward-open conformation to the cytosol. A short helix is located at the peroxisomal side, which is different from other three members of ABCD transporters. The two transmembrane domains (TMDs) of ALDP form a cavity, in which two lipid-like densities can be recognized as the head group of an coenzyme-A ester of a lipid. This structure provides a framework for understanding the working mechanism of ALDP and classification of the disease-causing mutations.

Learning the ABCs one at a time: structure and mechanism of ABC transporters

2019 ◽  
Vol 47 (1) ◽  
pp. 23-36 ◽  
Author(s):  
Robert C. Ford ◽  
Konstantinos Beis
Keyword(s):  
Abc Transporters ◽  
Atp Hydrolysis ◽  
Atp Binding ◽  
Bacterial Cells ◽  
The Novel ◽  
Mechanism Model ◽  
Binding Domains ◽  
Atp Binding And Hydrolysis ◽  
Alternating Access

Abstract ATP-binding cassette (ABC) transporters are essential proteins that are found across all kingdoms of life. ABC transporters harness the energy of ATP hydrolysis to drive the import of nutrients inside bacterial cells or the export of toxic compounds or essential lipids across bacteria and eukaryotic membranes. Typically, ABC transporters consist of transmembrane domains (TMDs) and nucleotide-binding domains (NBDs) to bind their substrate and ATP, respectively. The TMDs dictate what ligands can be recognised, whereas the NBDs are the power engine of the ABC transporter, carrying out ATP binding and hydrolysis. It has been proposed that they utilise the alternating access mechanism, inward- to outward-facing conformation, to transport their substrates. Here, we will review the recent progress on the structure determination of eukaryotic and bacterial ABC transporters as well as the novel mechanisms that have also been proposed, that fall out of the alternating access mechanism model.

Human Coagulation Factor Va Interaction with Phospholipid Vesicles: A Molecular Dynamics Study.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1699-1699
Author(s):  
Tivadar Orban ◽  
Michael Kalafatis
Keyword(s):  
Amino Acid ◽  
Lipid Bilayer ◽  
Factor Xa ◽  
Accessible Surface Area ◽  
Fatty Acyl ◽  
Phospholipid Bilayer ◽  
Solvent Accessible Surface Area ◽  
Factor Va ◽  
Accessible Surface ◽  
Simulation Time

Abstract The prothrombinase complex, the enzyme responsible for the timely conversion of prothrombin to thrombin, is composed of factor Xa (the enzyme), factor Va (the cofactor) assembled on the activated cell surface in the presence of divalent metal ions. In our quest to propose a model of the prothrombinase complex we first created a homology model in solution of factor Va (pdb code 1y61). Next we created a mixed phospholipid bilayer model composed of 1-palmitoyl, 2-oleoyl-sn-glycero-3-phosphatidylcholine (POPC) and 1-palmitoyl, 2-oleoyl-sn-glycero-3-phosphatidylserine (POPS) in a 4:1 ratio. The lipid bilayer was equilibrated for 10 ns. The data showed that the average area per head group and the deuterium order parameters of the fatty acyl chains compare well with the previously reported nuclear magnetic resonance data. We next created a system composed of factor Va, water molecules, phospholipid bilayer composed of POPS/POPC and sodium ions. Factor Va was placed at the near interface of the equilibrated POPC/POPS phospholipid bilayer but making sure that the two entities were not interacting. Molecular dynamics simulation was then performed on the entire system. Distance analysis performed between the center of masses of the factor Va molecule and the lipid bilayer revealed that during the 4.5 ns simulation time, the factor Va molecule gets inserted into the interface of the hydrophobic core of the bilayer. The distance between the two centers of masses decreased during the 4.5 ns simulation time from 92 Å to 78 Å. At the end of the 4.5 ns simulation time the indole moieties of Trp2063 and Trp2064 were found to be in the vicinity of the ester and the fatty acyl chain moieties of the phospholipids. Factor Va was found to participate in hydrogen bonds formation with both the carboxylate and the phosphate groups of POPS. Following 4.5 ns simulation time the farthest amino acid residue away from the membrane is located at ~ 100 Å from the lipid bilayer plane. This result is in agreement with previous fluorescence energy transfer studies that concluded that a domain of membrane-bound factor Va is positioned at a minimum distance of 90 Å above the membrane surface. It is noteworthy that the amino acid sequence comprising Pro1663 to Val1672 of factor Va had a root mean square displacemenent (RMSD) 4.5 times higher as the average RMSD of the other residues, i.e., 9 Å. This sequence is highly hydrophobic in nature and it was previously shown to contain a membrane binding site on factor Va. However, the present placement of factor Va on the lipid bilayer does not allow the insertion of this hydrophobic patch into the lipid bilayer. We next tested the hypothesis whether the region encompassing amino acid residues Glu323 to Val331 gets exposed to solvent following the interaction of factor Va with the phospholipids. This region was shown to contain a binding site of factor Xa on factor Va. Solvent accessible surface area calculated for each amino acid residue of the Glu323 to Val331 sequence revealed that during the 4.5 ns simulation time the solvent accessible surface area does not increase. In conclusion, our work proposes for the first time a model of factor Va bound to a mixed POPC/POPS lipid bilayer and provides the necessary framework that accounts for the presence of phospholipids as a major regulatory component of a protein complex. This model can be extrapolated to the study of the dynamics of other membrane associated complexes involved in blood coagulation.

Labeling of the ATP synthase of Escherichia coli from the head-group region of the lipid bilayer

Biochemistry ◽  
1987 ◽  
Vol 26 (22) ◽  
pp. 7107-7113 ◽  
Author(s):  
Robert Aggeler ◽  
Yu Zhong Zhang ◽  
Roderick A. Capaldi
Keyword(s):  
Escherichia Coli ◽  
Lipid Bilayer ◽  
Atp Synthase ◽  
Head Group

scholarly journals Crystal structure and mechanistic basis of a functional homolog of the antigen transporter TAP

2017 ◽  
Vol 114 (4) ◽  
pp. E438-E447 ◽  
Author(s):  
Anne Nöll ◽  
Christoph Thomas ◽  
Valentina Herbring ◽  
Tina Zollmann ◽  
Katja Barth ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Conformational Changes ◽  
Abc Transporters ◽  
Antigen Processing ◽  
Thermus Thermophilus ◽  
Multidrug Resistance Proteins ◽  
Atp Binding Site ◽  
Functional Homolog ◽  
Domains Of Life ◽  
Mechanistic Basis

ABC transporters form one of the largest protein superfamilies in all domains of life, catalyzing the movement of diverse substrates across membranes. In this key position, ABC transporters can mediate multidrug resistance in cancer therapy and their dysfunction is linked to various diseases. Here, we describe the 2.7-Å X-ray structure of heterodimeric Thermus thermophilus multidrug resistance proteins A and B (TmrAB), which not only shares structural homology with the antigen translocation complex TAP, but is also able to restore antigen processing in human TAP-deficient cells. TmrAB exhibits a broad peptide specificity and can concentrate substrates several thousandfold, using only one single active ATP-binding site. In our structure, TmrAB adopts an asymmetric inward-facing state, and we show that the C-terminal helices, arranged in a zipper-like fashion, play a crucial role in guiding the conformational changes associated with substrate transport. In conclusion, TmrAB can be regarded as a model system for asymmetric ABC exporters in general, and for TAP in particular.

scholarly journals Structure of MlaFB uncovers novel mechanisms of ABC transporter regulation

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Ljuvica R Kolich ◽  
Ya-Ting Chang ◽  
Nicolas Coudray ◽  
Sabrina I Giacometti ◽  
Mark R MacRae ◽  
...  
Keyword(s):  
Abc Transporter ◽  
Abc Transporters ◽  
Membrane Integrity ◽  
Regulatory Mechanisms ◽  
Nucleotide Binding Domain ◽  
E Coli ◽  
Small Proteins ◽  
Transporter Family ◽  
Bacterial Lipid ◽  
Lipid Transporter

ABC transporters facilitate the movement of diverse molecules across cellular membranes, but how their activity is regulated post-translationally is not well understood. Here we report the crystal structure of MlaFB from E. coli, the cytoplasmic portion of the larger MlaFEDB ABC transporter complex, which drives phospholipid trafficking across the bacterial envelope to maintain outer membrane integrity. MlaB, a STAS domain protein, binds the ABC nucleotide binding domain, MlaF, and is required for its stability. Our structure also implicates a unique C-terminal tail of MlaF in self-dimerization. Both the C-terminal tail of MlaF and the interaction with MlaB are required for the proper assembly of the MlaFEDB complex and its function in cells. This work leads to a new model for how an important bacterial lipid transporter may be regulated by small proteins, and raises the possibility that similar regulatory mechanisms may exist more broadly across the ABC transporter family.

scholarly journals Leaf Lipid Alterations in Response to Heat Stress of Arabidopsis thaliana

Plants ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 845 ◽  
Author(s):  
Sunitha Shiva ◽  
Thilani Samarakoon ◽  
Kaleb A. Lowe ◽  
Charles Roach ◽  
Hieu Sy Vu ◽  
...  
Keyword(s):  
Arabidopsis Thaliana ◽  
Heat Stress ◽  
Elevated Temperatures ◽  
Membrane Lipids ◽  
Fatty Acyl ◽  
Head Group ◽  
Wild Type ◽  
Lipid Levels ◽  
Acyl Chains ◽  
Severe Heat Stress

In response to elevated temperatures, plants alter the activities of enzymes that affect lipid composition. While it has long been known that plant leaf membrane lipids become less unsaturated in response to heat, other changes, including polygalactosylation of galactolipids, head group acylation of galactolipids, increases in phosphatidic acid and triacylglycerols, and formation of sterol glucosides and acyl sterol glucosides, have been observed more recently. In this work, by measuring lipid levels with mass spectrometry, we confirm the previously observed changes in Arabidopsis thaliana leaf lipids under three heat stress regimens. Additionally, in response to heat, increased oxidation of the fatty acyl chains of leaf galactolipids, sulfoquinovosyldiacylglycerols, and phosphatidylglycerols, and incorporation of oxidized acyl chains into acylated monogalactosyldiacylglycerols are shown. We also observed increased levels of digalactosylmonoacylglycerols and monogalactosylmonoacylglycerols. The hypothesis that a defect in sterol glycosylation would adversely affect regrowth of plants after a severe heat stress regimen was tested, but differences between wild-type and sterol glycosylation-defective plants were not detected.

Sign in / Sign up

Export Citation Format

Share Document