On the interplay between lipids and asymmetric dynamics of an NBS degenerate ABC transporter

Tóth, Ágota; Janaszkiewicz, Angelika; Crespi, Veronica; Meo, Florent Di

doi:10.1038/s42003-023-04537-3

Cited by 10 publications

(5 citation statements)

References 73 publications

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“…TmrAB was captured in five conformations that were proposed to represent the ATPpowered cycle 12 . However, as noted previously by us 11 and others 27,32 , the energetics of the TmrAB conformational cycle may not be reflective of the typical type IV exporter.…”

Section: Introductionmentioning

confidence: 67%

“…One of the remarkable variations on the theme of ATP energy conversion in ABC transporters is the evolution of heterodimeric ABC exporters 27,28 . In addition to mediating drug resistance in prokaryotes and important physiological roles in humans, heterodimeric ABC transporters are distinguished by having an intrinsically asymmetric ATP catalytic cycle resulting from the selective substitution of one of the catalytic glutamates in the NBD 12,29,30 .…”

Section: Introductionmentioning

confidence: 99%

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Asymmetric conformations and lipid interactions shape the ATP-coupled cycle of a heterodimeric ABC transporter

Tang

Sinclair

Hasdemir

et al. 2023

Preprint

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Heterodimeric ATP-binding cassette (ABC) transporters represent a unique paradigm of ATP energy transduction wherein a catalytically asymmetric ATP hydrolysis cycle in the nucleotide-binding domains powers alternating access in the transmembrane domains. The structural origin of the asymmetry and how it shapes the energetics of the conformational cycle are yet to be elucidated. Here, we used cryo-electron microscopy (cryo-EM), double electron-electron resonance spectroscopy (DEER) and molecular dynamics (MD) simulations, to capture multiple conformations of the heterodimeric ABC multidrug exporter BmrCD in lipid nanodiscs at near-atomic resolution. In addition to multiple ATP- and substrate-bound inward-facing (IF) conformations, we obtained the structure of an occluded (OC) conformation wherein the unique extracellular domain (ECD) twists to partially open the extracellular gate. In conjunction with DEER analysis of the populations of these conformations, the structures reveal that ATP-powered isomerization of the transporter entails changes in the relative symmetry of the BmrC and BmrD subunits that propagates from the transmembrane domain (TMD) to the nucleotide binding domain (NBD) thereby modulating Mg2+ binding and triggering ATP hydrolysis preferentially in the one of the nucleotide-binding sites. MD simulations demonstrated that multiple lipid molecules identified from the cryo-EM density maps differentially bind the IF versus the OC conformations, thus rationalizing the reduced efficiency of coupling ATP hydrolysis in the NBD to alternating access of the TMD in lipid bilayers. In addition to establishing how lipid interactions with BmrCD modulate the energy landscape, our findings are framed in a distinct transport model that highlights the role of asymmetric conformations in the ATP-coupled cycle with implications to the mechanism of ABC transporters in general.

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Section: Introductionmentioning

confidence: 67%

Section: Introductionmentioning

confidence: 99%

Asymmetric conformations and lipid interactions shape the ATP-coupled cycle of a heterodimeric ABC transporter

Tang

Sinclair

Hasdemir

et al. 2023

Preprint

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“…The model is called “ball-and-socket”, where the CH of TMD (ball) interacts with the surface of an NBD’s cleft (socket). Therefore, there are fewer interactions between NBD1 and TMD due to the absence of 13 residues in the socket of NBD1 [ 57 , 127 ].…”

Section: Alternating Access Mechanism In Mammalian Mdrs and Bacterial...mentioning

confidence: 99%

The Alternating Access Mechanism in Mammalian Multidrug Resistance Transporters and Their Bacterial Homologs

et al. 2023

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Multidrug resistance (MDR) proteins belonging to the ATP-Binding Cassette (ABC) transporter group play a crucial role in the export of cytotoxic drugs across cell membranes. These proteins are particularly fascinating due to their ability to confer drug resistance, which subsequently leads to the failure of therapeutic interventions and hinders successful treatments. One key mechanism by which multidrug resistance (MDR) proteins carry out their transport function is through alternating access. This mechanism involves intricate conformational changes that enable the binding and transport of substrates across cellular membranes. In this extensive review, we provide an overview of ABC transporters, including their classifications and structural similarities. We focus specifically on well-known mammalian multidrug resistance proteins such as MRP1 and Pgp (MDR1), as well as bacterial counterparts such as Sav1866 and lipid flippase MsbA. By exploring the structural and functional features of these MDR proteins, we shed light on the roles of their nucleotide-binding domains (NBDs) and transmembrane domains (TMDs) in the transport process. Notably, while the structures of NBDs in prokaryotic ABC proteins, such as Sav1866, MsbA, and mammalian Pgp, are identical, MRP1 exhibits distinct characteristics in its NBDs. Our review also emphasizes the importance of two ATP molecules for the formation of an interface between the two binding sites of NBD domains across all these transporters. ATP hydrolysis occurs following substrate transport and is vital for recycling the transporters in subsequent cycles of substrate transportation. Specifically, among the studied transporters, only NBD2 in MRP1 possesses the ability to hydrolyze ATP, while both NBDs of Pgp, Sav1866, and MsbA are capable of carrying out this reaction. Furthermore, we highlight recent advancements in the study of MDR proteins and the alternating access mechanism. We discuss the experimental and computational approaches utilized to investigate the structure and dynamics of MDR proteins, providing valuable insights into their conformational changes and substrate transport. This review not only contributes to an enhanced understanding of multidrug resistance proteins but also holds immense potential for guiding future research and facilitating the development of effective strategies to overcome multidrug resistance, thus improving therapeutic interventions.

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Section: Introductionmentioning

confidence: 99%

“…Molecular dynamics simulations are known to be a valuable tool for detailed atomic-level studies of proteins and membrane transporters [32–34]. Numerous MD simulations have been conducted to investigate the dynamics of various ABC transporters [5–7, 9, 10, 32, 34, 39, 47]. To our knowledge, this study represents the first comprehensive computational exploration into how the presence of DMPC lipids influences Sav1866’s alternating access mechanism.…”

Section: Introductionmentioning

confidence: 99%

Lipid-dependent conformational dynamics of bacterial ATP-binding cassette transporter Sav1866

Badiee,

Hettige,

Moradi

2024

Preprint

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Sav1866, a bacterial ATP-binding cassette (ABC) exporter, plays a crucial role in cellular processes by facilitating the efflux of a diverse range of substrates, including drugs, chemotherapeutic agents, peptides, and lipids. This efflux activity significantly impacts the effectiveness of various therapies against bacterial infections. In our recent investigation, we focused on understanding the conformational dynamics of Sav1866 within different lipid environments. Specifically, we explored its behavior in environments composed of DMPC and POPE lipids, which exhibit crucial distinctions not only in their headgroup polarity but also in the length and saturation of their hydrophobic tails. Our extensive set of equilibrium microsecond-level all-atom molecular dynamics (MD) simulations revealed significant distinctions in transporter behavior influenced by these lipid compositions. We observed a rapid transition to an occluded-inward-facing (IF-occ) conformation in POPE environments, contrasting with a channel-like behavior in DMPC environments, deviating from the expected alternating access mechanism (AAM). These findings underscore the significant impact of lipid compositions on ABC transporter function, offering new perspectives on membrane transport mechanisms.

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On the interplay between lipids and asymmetric dynamics of an NBS degenerate ABC transporter

Cited by 10 publications

References 73 publications

Asymmetric conformations and lipid interactions shape the ATP-coupled cycle of a heterodimeric ABC transporter

Asymmetric conformations and lipid interactions shape the ATP-coupled cycle of a heterodimeric ABC transporter

The Alternating Access Mechanism in Mammalian Multidrug Resistance Transporters and Their Bacterial Homologs

Lipid-dependent conformational dynamics of bacterial ATP-binding cassette transporter Sav1866

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