Dataset Information

Molecular insights into the human ABCB6 transporter.

ABSTRACT: 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.

SUBMITTER: Song G

PROVIDER: S-EPMC8313675 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Molecular insights into the human ABCB6 transporter.

Song Guangyuan G Zhang Sensen S Tian Mengqi M Zhang Laixing L Guo Runyu R Zhuo Wei W Yang Maojun M

Cell discovery 20210727 1

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 structure ...[more]

PMID: 34312373

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Project description:BackgroundThe monocarboxylate transporter 8 (MCT8) is a member of the major facilitator superfamily (MFS) and transports specificly iodothyronines. MCT8 mutations are the underlying cause of a syndrome of severe X-linked psychomotor retardation known as the Allan-Herndon-Dudley syndrome. This syndrome is characterized by abnormally high T3, low/normal T4 serum levels and slightly elevated serum TSH. To date, more than 25 pathogenic mutations in hMCT8 are known and they are valuable indicators of important regions for structural and functional MCT8 properties.MethodsWe designed a structural human MCT8 model and studied reported pathogenic missense mutations with focus on the estimation of those amino acid positions which are probably sensitive for substrate transport. Furthermore, assuming similarities between determinants of T3 binding observed in the published crystal structure of the thyroid hormone receptor beta occupied by its ligand T3 and the structural MCT8 model, we explore potential T3 binding sites in the MCT8 substrate channel cavity.ResultsWe found that all known pathogenic missense mutations are located exclusively in the transmembrane helices and to a high degree at conserved residues among the MCT family. Furthermore, mutations either of or to prolines/glycines are located mainly at helices 9-12 and are expected to cause steric clashes or structural misfolding. In contrast, several other mutations are close to the potential substrate channel and affected amino acids are likely involved in the switching mechanism between different transporter conformations. Finally, three potential substrate binding sites are predicted for MCT8.ConclusionsNaturally occurring mutations of MCT8 provide molecular insights into protein regions important for protein folding, substrate binding and the switching mechanism during substrate transport. Future studies guided by this information should help to clarify structure-function relationships at MCT8 which may bear broader relevance for other members of the MCT family. This includes decoding of the complete set of transport-sensitive residue positions and description of structural re-arrangements during transport.

Dataset Information

Molecular insights into the human ABCB6 transporter.

Publications

Molecular insights into the human ABCB6 transporter.

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