<scp>Cryo‐</scp>electron microscopy structure of human <scp>ABCB6</scp> transporter

Wang, Chunyu; Cao, Chuanai; Wang, Nan; Wang, Xiangxi; Zhang, Xuejun C.

doi:10.1002/pro.3960

Cited by 26 publications

(27 citation statements)

References 48 publications

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“…The molecular mechanisms of transmembrane transportation and substrate recognition for ABCB6 remain unclear, as well as the mechanism underlying pathogenic mutations and drug resistance. Recently, Wang et al 23 reported the cryo-EM structure of human ABCB6 and provided a structural glimpse of this transporter. However, this study mainly bases on a 4.0-Å resolution model, which is borderline sufficient to identify side chains.…”

Section: Introductionmentioning

confidence: 99%

Molecular insights into the human ABCB6 transporter

et al. 2021

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ABCB6 plays a crucial role in energy-dependent porphyrin transport, drug resistance, toxic metal resistance, porphyrin biosynthesis, protection against stress, and encoding a blood group system Langereis antigen. However, the mechanism underlying porphyrin transport is still unclear. Here, we determined the cryo-electron microscopy (cryo-EM) structures of nanodisc-reconstituted human ABCB6 trapped in an apo-state and an ATP-bound state at resolutions of 3.6 and 3.5 Å, respectively. Our structures reveal a unique loop in the transmembrane domain (TMD) of ABCB6, which divides the TMD into two cavities. It restrains the access of substrates in the inward-facing state and is removed by ATP-driven conformational change. No ligand cavities were observed in the nucleotide-bound state, indicating a state following substrate release but prior to ATP hydrolysis. Structural analyses and functional characterizations suggest an “ATP-switch” model and further reveal the conformational changes of the substrate-binding pockets triggered by the ATP-driven regulation.

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Section: Introductionmentioning

confidence: 99%

Molecular insights into the human ABCB6 transporter

et al. 2021

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“…The other well-resolved segment of the R region is located on the peripheral face of NBD1, opposite the ATP binding and NBD dimerization interfaces (Fig. 3A, right (9,10,(12)(13)(14).…”

Section: Regulatory (R) Region Interactions Explain Its Regulatory Rolementioning

confidence: 99%

“…A TMD0, but not L0 linker, is also found in some ABCB proteins (3,5). These Nterminal extensions are involved in trafficking, endosomal recycling, protein interactions, and/or regulation of ABC activity (9)(10)(11)(12)(13)(14)(15)(16)(17)(18). The existence of disease-causing mutations in TMD0 and L0 linker of different ABCC proteins (8,13,18) indicates that TMD0 and the L0 linker play important roles in protein function when present.…”

Section: Introductionmentioning

confidence: 99%

“…High-resolution structural information for TMD0 is available only for the atypical ABCC protein SUR1 (19,20), which is part of the large hetero-octameric ATP-sensitive K+ (KATP) channel complex. In contrast, structures of monomeric ABC transporters showed only lowresolution density for TMD0 that was insufficient for building a full atomic model or lacked density for the domain altogether (14,(21)(22)(23)(24). The vacuolar ABCC protein yeast cadmium factor 1 (Ycf1p) from Saccharomyces cerevisiae is a close homologue of human MRPs and a model for ABCC proteins that function as monomers.…”

Section: Introductionmentioning

confidence: 99%

“…Considering the small number of contacts between TMD0 and other regions of the transporter, even a single mutation would alter how TMD0 interacts with the rest of the ABC transporter. Destabilization of TMD0 and/or altered TMD0/TM helix bundle 1 contacts could have implications for MRP6 trafficking and protein-protein interactions, due to this role for TMD0 in ABC proteins(9,10,(12)(13)(14).…”

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Structure of Ycf1p reveals the transmembrane domain TMD0 and the regulatory R region of ABCC transporters

Bickers

Rubinstein

Kanelis

2021

Preprint

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ATP binding cassette (ABC) proteins typically function in active transport of solutes across membranes. The ABC core structure is comprised of two transmembrane domains (TMD1 and TMD2) and two cytosolic nucleotide binding domains (NBD1 and NBD2). Some members of the C-subfamily of ABC (ABCC) proteins, including human multidrug resistance proteins (MRPs), also possess an N-terminal transmembrane domain (TMD0) that contains five transmembrane α-helices and is connected to the ABC core by the L0 linker. While TMD0 was resolved in SUR1, the atypical ABCC protein that is part of the hetero-octameric ATP-sensitive K+ channel, little is known about the structure of TMD0 in monomeric ABC transporters. Here, we present the structure of yeast cadmium factor 1 protein (Ycf1p), a homologue of human MRP1, determined by electron cryomicroscopy (cryo-EM). Comparison of Ycf1p, SUR1, and a structure of MRP1 that showed TMD0 at low resolution demonstrates that TMD0 can adopt different orientations relative to the ABC core, including a 145° rotation between Ycf1p and SUR1. The cryo-EM map also reveals that segments of the regulatory (R) region, which links NBD1 to TMD2 and was poorly resolved in earlier ABCC structures, interacts with the L0 linker, NBD1, and TMD2. These interactions, combined with fluorescence quenching experiments of isolated NBD1 with and without the R region, suggests how post-translational modifications of the R region modulate ABC protein activity. Mapping known mutations from MRP2 and MRP6 onto the Ycf1p structure explains how mutations involving TMD0 and the R region of these proteins lead to disease.Statement of SignificanceThe Ycf1p structure provides an atomic model for the TMD0 domain of ABCC transporters and for two segments of the regulatory (R) region that links NBD1 to TMD2. The orientation of TMD0 in Ycf1p differs from that seen in SUR1, the regulatory ABCC protein in KATP channels, demonstrating flexibility in TMD0/ABC core contacts. The structure suggests how post-translational modifications of the R region modulate ABC protein activity and provides a mechanistic understanding of several diseases that occur due to mutation of human homologues of Ycf1p.

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Plastic structures for diverse substrates: A revisit of human ABC transporters

Hou

Wang

et al. 2022

Proteins

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ATP-binding cassette (ABC) superfamily is one of the largest groups of primary active transporters that could be found in all kingdoms of life from bacteria to humans. In humans, ABC transporters can selectively transport a wide spectrum of substrates across membranes, thus playing a pivotal role in multiple physiological processes. In addition, due to the ability of exporting clinic therapeutics, some ABC transporters were originally termed multidrug resistance proteins. Increasing investigations of human ABC transporters in recent years have provided abundant information for elucidating their structural features, based on the structures at distinct states in a transport cycle. This review focuses on the recent progress in human ABC structural analyses, substrate binding specificities, and translocation mechanisms. We dedicate to summarize the common features of human ABC transporters in different subfamilies, and to discuss the possibility to apply the fast-developing techniques, such as cryogenic electron microscopy, and artificial intelligence-assisted structure prediction, for future studies.

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Cryo‐electron microscopy structure of human ABCB6 transporter

Cited by 26 publications

References 48 publications

Molecular insights into the human ABCB6 transporter

Molecular insights into the human ABCB6 transporter

Structure of Ycf1p reveals the transmembrane domain TMD0 and the regulatory R region of ABCC transporters

Plastic structures for diverse substrates: A revisit of human ABC transporters

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