Molecular insights into the human ABCB6 transporter

Song, Guangyuan; Zhang, Sensen; Tian, Mengqi; Zhang, Laixing; Guo, Runyu; Zhuo, Wei; Yang, Maojun

doi:10.1038/s41421-021-00284-z

Cited by 21 publications

(17 citation statements)

References 65 publications

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“…1A ). In agreement with the results of previous studies ( Song et al, 2021 ; Wang et al, 2020 ), our data indicated that at saturating concentrations (100 µM PPIX or 50 µM CPIII), the metal-free porphyrins modestly stimulated the ATPase activity of ABCB6-∆TMD0 approximately 2- to 3-fold ( Figs. 1B and 1C ).…”

Section: Resultssupporting

confidence: 93%

“…2A and 2B), but the TMDs swing towards each other (~4°), resulting in a somewhat reduced separation between the two NBDs (Fig. 2C) (Song et al, 2021;Wang et al, 2020). The most significant structural changes are concentrated near the central cavity where we could assess the EM density of CPIII at the inner leaflet-cytosol interface (Fig.…”

Section: Model Building Strategy Of Cpiii Bound To Abcb6-∆tmd0mentioning

confidence: 98%

“…Recently, cryo-electron microscopy (cryo-EM) structures of human ABCB6 have been reported, with the enzyme in its apo form and in complex with ATP (Song et al, 2021;Wang et al, 2020). However, understanding the mechanisms of substrate recognition and specificity is still challenging due to the lack of substrate-bound structures.…”

Section: Introductionmentioning

confidence: 99%

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Structural Insights into Porphyrin Recognition by the Human ATP-Binding Cassette Transporter ABCB6

Kim

Lee

Park

et al. 2022

Molecules and Cells

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Human ABCB6 is an ATP-binding cassette transporter that regulates heme biosynthesis by translocating various porphyrins from the cytoplasm into the mitochondria. Here we report the cryo-electron microscopy (cryo-EM) structures of human ABCB6 with its substrates, coproporphyrin III (CPIII) and hemin, at 3.5 and 3.7 Å resolution, respectively. Metalfree porphyrin CPIII binds to ABCB6 within the central cavity, where its propionic acids form hydrogen bonds with the highly conserved Y550. The resulting structure has an overall fold similar to the inward-facing apo structure, but the two nucleotide-binding domains (NBDs) are slightly closer to each other. In contrast, when ABCB6 binds a metal-centered porphyrin hemin in complex with two glutathione molecules (1 hemin: 2 glutathione), the two NBDs end up much closer together, aligning them to bind and hydrolyze ATP more efficiently. In our structures, a glycine-rich and highly flexible "bulge" loop on TM helix 7 undergoes significant conformational changes associated with substrate binding. Our findings suggest that ABCB6 utilizes at least two distinct mechanisms to fine-tune substrate specificity and transport efficiency.

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Section: Resultssupporting

confidence: 93%

Section: Model Building Strategy Of Cpiii Bound To Abcb6-∆tmd0mentioning

confidence: 98%

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Structural Insights into Porphyrin Recognition by the Human ATP-Binding Cassette Transporter ABCB6

Kim

Lee

Park

et al. 2022

Molecules and Cells

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“…This structure revealed an inward-facing conformation for At Atm3 similar to those observed for the inward-facing conformations for Sc Atm1 (PDB ID: 4myc) and Na Atm1 (PDB ID: 6vqu) with overall alignment root mean square deviations (rmsds) for the dimer of 2.6 Å ( Figure 2—figure supplement 2a, b ) and 2.1 Å ( Figure 2 ), respectively, and half-transporter alignment rmsds of 2.3 and 2.0 Å ( Figure 2—figure supplement 2c ), respectively. The primary distinction between these structures is the presence of an approximately 20 amino acid loop between TM1 and TM2 of At Atm3 that would be positioned in the intermembrane space and is absent from the structures of ABCB7 ( Jumper et al, 2021 ; Varadi et al, 2022 ), ABCB6 ( Song et al, 2021 ), Sc Atm1 ( Srinivasan et al, 2014 ), and Na Atm1 ( Lee et al, 2014 ; Figure 2—figure supplement 3 ). While the functional relevance of this loop in At Atm3 is not known, structural characterization of PglK, a lipid-linked oligosaccharide flippase, revealed a comparably positioned external helix between TM1 and TM2 that was implicated in substrate flipping ( Perez et al, 2015 ), suggestive that the corresponding loop could also have a functional or structural role in At Atm3.…”

Section: Resultsmentioning

confidence: 99%

Glutathione binding to the plant AtAtm3 transporter and implications for the conformational coupling of ABC transporters

Fan

Rees

2022

eLife

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The ATP Binding Cassette (ABC) transporter of mitochondria (Atm) from Arabidopsis thaliana (AtAtm3) has been implicated in the maturation of cytosolic iron-sulfur proteins and heavy metal detoxification, plausibly by exporting glutathione derivatives. Using single-particle cryo-electron microscopy, we have determined four structures of AtAtm3 in three different conformational states: two inward-facing conformations (with and without bound oxidized glutathione (GSSG)), together with closed and outward-facing states stabilized by MgADP-VO4. These structures not only provide a structural framework for defining the alternating access transport cycle, but also reveal the paucity of cysteine residues in the glutathione binding site that could potentially form inhibitory mixed disulfides with GSSG. Despite extensive efforts, we were unable to prepare the ternary complex of AtAtm3 containing both GSSG and MgATP. A survey of structurally characterized type IV ABC transporters that includes AtAtm3 establishes that while nucleotides are found associated with all conformational states, they are effectively required to stabilize occluded, closed, and outward-facing conformations. In contrast, transport substrates have only been observed associated with inward-facing conformations. The absence of structures with dimerized nucleotide binding domains containing both nucleotide and transport substrate suggests that this form of the ternary complex exists only transiently during the transport cycle.

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“…In addition to oxidative damage, mitochondrial failure in AHP could also be driven by cytochrome dysfunction due to heme depletion. Of note, heme is yielded in mitochondria: following an initial series of reactions in the cytosol, coproporphyrin III is imported in mitochondria by ABCB6, a homodimeric porphyrin transporter located in the outer mitochondrial membrane, to undergo the final steps of heme biosynthesis [ 96 ]. Several alterations in brain oxidative phosphorylation have been reported in T1/T2 mice, with an increase of Complex II activity in the basal state, and a significant reduction of all four complexes after treatment with phenobarbital, compared to wild-type controls [ 97 ].…”

Section: Heme Deficiency-induced Dysfunctionmentioning

confidence: 99%

Mechanisms of Neuronal Damage in Acute Hepatic Porphyrias

et al. 2021

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Porphyrias are a group of congenital and acquired diseases caused by an enzymatic impairment in the biosynthesis of heme. Depending on the specific enzyme involved, different types of porphyrias (i.e., chronic vs. acute, cutaneous vs. neurovisceral, hepatic vs. erythropoietic) are described, with different clinical presentations. Acute hepatic porphyrias (AHPs) are characterized by life-threatening acute neuro-visceral crises (acute porphyric attacks, APAs), featuring a wide range of neuropathic (central, peripheral, autonomic) manifestations. APAs are usually unleashed by external “porphyrinogenic” triggers, which are thought to cause an increased metabolic demand for heme. During APAs, the heme precursors δ-aminolevulinic acid (ALA) and porphobilinogen (PBG) accumulate in the bloodstream and urine. Even though several hypotheses have been developed to explain the protean clinical picture of APAs, the exact mechanism of neuronal damage in AHPs is still a matter of debate. In recent decades, a role has been proposed for oxidative damage caused by ALA, mitochondrial and synaptic ALA toxicity, dysfunction induced by relative heme deficiency on cytochromes and other hemeproteins (i.e., nitric oxide synthases), pyridoxal phosphate functional deficiency, derangements in the metabolic pathways of tryptophan, and other factors. Since the pathway leading to the biosynthesis of heme is inscribed into a complex network of interactions, which also includes some fundamental processes of basal metabolism, a disruption in any of the steps of this pathway is likely to have multiple pathogenic effects. Here, we aim to provide a comprehensive review of the current evidence regarding the mechanisms of neuronal damage in AHPs.

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Molecular insights into the human ABCB6 transporter

Cited by 21 publications

References 65 publications

Structural Insights into Porphyrin Recognition by the Human ATP-Binding Cassette Transporter ABCB6

Structural Insights into Porphyrin Recognition by the Human ATP-Binding Cassette Transporter ABCB6

Glutathione binding to the plant AtAtm3 transporter and implications for the conformational coupling of ABC transporters

Mechanisms of Neuronal Damage in Acute Hepatic Porphyrias

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