Molecular basis of cholesterol efflux via ABCG subfamily transporters

Sun, Yingyuan; Wang, Jin; Long, Tao; Qi, Xiaofeng; Donnelly, Linda; Elghobashi-Meinhardt, Nadia; Esparza, Leticia; Cohen, Jonathan C.; Xie, Xiao‐Song; Hobbs, Helen H.; Li, Xiaochun

doi:10.1073/pnas.2110483118

Cited by 55 publications

(83 citation statements)

References 48 publications

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“…One signature residue (D466 of ABCG8) makes contact with sterol in site 1. This site is also observed in the structure of ABCG1 that binds sterols in a similar fashion (pdb: 7R8D) 47 and involves a similar set of binding residues from TMH2 and TMH5 (marked by green asterisks above the human ABCG1 in Figure 2). The second sterol‐binding site (site 2) of ABCG5/ABCG8 is located midway through the TMHs, and the orientation of sterol molecule (shown in red in Figure 4) is nearly parallel to the membrane.…”

Section: Resultsmentioning

confidence: 60%

“…A recent structure of the ABCG5/ABCG8 complex showed two sterol molecules binding at two sites located in the interface between ABCG5 and ABCG8 TMDs (PDB: 7R8B) 47 . The first site (site 1 47 ) is located within the cytosolic leaflet of the membrane and contains a sterol (shown in green in Figure 4) positioning in parallel to the transmembrane helices. Sterol‐contacting residues (within 5 Å) at site 1 are mainly from TMH2 of ABCG8 and TMH5 of ABCG5 (marked by green asterisks in Figure 2).…”

Section: Resultsmentioning

confidence: 99%

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Evolutionary origin and sequence signatures of the heterodimeric ABCG5/ABCG8 transporter

Pei

Cong

2022

Protein Science

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ATP‐binding cassette (ABC) systems, characterized by ABC‐type nucleotide‐binding domains (NBDs), play crucial roles in various aspects of human physiology. Human ABCG5 and ABCG8 form a heterodimeric transporter that functions in the efflux of sterols. We used sequence similarity search, multiple sequence alignment, phylogenetic analysis, and structure comparison to study the evolutionary origin and sequence signatures of ABCG5 and ABCG8. Orthologs of ABCG5 and ABCG8, supported by phylogenetic analysis and signature residues, were identified in bilaterian animals, Filasterea, Fungi, and Amoebozoa. Such a phylogenetic distribution suggests that ABCG5 and ABCG8 could have originated in the last common ancestor of Amorphea (the unikonts), the eukaryotic group including Amoebozoa and Opisthokonta. ABCG5 and ABCG8 were missing in genomes of various lineages such as snakes, jawless vertebrates, non‐vertebrate chordates, echinoderms, and basal metazoan groups. Amino‐acid changes in key positions in ABCG8 Walker A motif and/or ABCG5 C‐loop were observed in most tetrapod organisms, likely resulted in the loss of ATPase activity at one nucleotide‐binding site. ABCG5 and ABCG8 in Ecdysozoa (such as insects) exhibit elevated evolutionary rates and accumulate various changes in their NBD functional motifs. Alignment inspection revealed several residue positions that show different amino‐acid usages in ABCG5/ABCG8 compared to other ABCG subfamily proteins. These residues were mapped to the structural cores of transmembrane domains (TMDs), the NBD‐TMD interface, and the interface between TMDs. They serve as sequence signatures to differentiate ABCG5/ABCG8 from other ABCG subfamily proteins, and some of them may contribute to substrate specificity of the ABCG5/ABCG8 transporter.

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Section: Resultsmentioning

confidence: 60%

Section: Resultsmentioning

confidence: 99%

Evolutionary origin and sequence signatures of the heterodimeric ABCG5/ABCG8 transporter

Pei

Cong

2022

Protein Science

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“…These LXRs act as ligand-activated transcription factors [ 42 ], binding to the promoter region of ATP-binding cassette transporters (ABC transporters), leading to the expression of ABCA1 and ABCG1 [ 42 ]. ABCA1 and ABCG1 can control the levels of cholesterol in-and-out of cells [ 43 ]. Little is known about the effect of EEF2K inhibition on the LXR ligands but SREBP2 can increase ABCA1 expression by maintaining the supply of endogenous oxysterol ligands for LXR through the mevalonate pathway [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

Targeting Protein Translation in Melanoma by Inhibiting EEF-2 Kinase Regulates Cholesterol Metabolism though SREBP2 to Inhibit Tumour Development

Dinavahi

Chen

Gowda

et al. 2022

IJMS

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Decreasing the levels of certain proteins has been shown to be important for controlling cancer but it is currently unknown whether proteins could potentially be targeted by the inhibiting of protein synthesis. Under this circumstance, targeting protein translation could preferentially affect certain pathways, which could then be of therapeutic advantage when treating cancer. In this report, eukaryotic elongation factor-2 kinase (EEF2K), which is involved in protein translation, was shown to regulate cholesterol metabolism. Targeting EEF2K inhibited key parts of the cholesterol pathway in cancer cells, which could be rescued by the addition of exogenous cholesterol, suggesting that it is a potentially important pathway modulated by targeting this process. Specifically, targeting EEF2K significantly suppressed tumour cell growth by blocking mRNA translation of the cholesterol biosynthesis transcription factor, sterol regulatory element-binding protein (SREBP) 2, and the proteins it regulates. The process could be rescued by the addition of LDL cholesterol taken into the cells via non-receptor-mediated-uptake, which negated the need for SREBP2 protein. Thus, the levels of SREBP2 needed for cholesterol metabolism in cancer cells are therapeutically vulnerable by targeting protein translation. This is the first report to suggest that targeting EEF2K can be used to modulate cholesterol metabolism to treat cancer.

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“…The biosynthesis of cholesterol is a well-defined energy-consuming and feedback-regulated process ( Howe et al, 2016 ). ATP-binding cassette transporters G5 ( ABCG5 gene) and G8 ( ABCG8 gene) usually form a heterodimer (G5G8) which inhibits the absorption of cholesterol and plant sterols by promoting the efflux of these sterols from enterocytes back into the gut lumen, and the secretions from hepatocytes into bile ( Wang et al, 2015 ; Lee et al, 2016 ; Sun et al, 2021 ). In contrast, sterol transporter Niemann–PickC1-Like1 (NPC1L1) promotes intestinal cholesterol absorption and biliary cholesterol re-absorption ( Jia et al, 2011 ).…”

Section: Introductionmentioning

confidence: 99%

Remediation of ABCG5-Linked Macrothrombocytopenia With Ezetimibe Therapy

Deng

Chen

et al. 2021

Front. Genet.

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To investigate refractory hypercholesterolemia, a female patient and relatives were subjected to whole-genome sequencing. The proband was found to have compound heterozygous substitutions p. Arg446Gln and c.1118+3G>T in ABCG5, one of two genes causing sitosterolemia. When tracing these variants in the full pedigree, all maternally related heterozygotes for the intronic ABCG5 variant exhibited large platelets (over 30 fl), which segregated in an autosomal dominant manner, consistent with macrothrombocytopenia, or large platelet syndrome which may be associated with a bleeding tendency. In vitro cell-line and in vivo rat model experiments supported a pathogenic role for the variant and the macrothrombocytopenia was recapitulated in heterozygous rats and human cell lines exhibiting that single variant. Ezetimibe treatment successfully ameliorated all the symptoms of the proband with sitosterolemia and resolved the macrothrombocytopenia of the treated heterozygote relatives. Subsequently, in follow up these observations, platelet size, and size distribution were measured in 1,180 individuals; 30 were found to be clinically abnormal, three of which carried a single known pathogenic ABCG5 variant (p.Arg446Ter) and two individuals carried novel ABCG5 variants of uncertain significance. In this study, we discovered that identification of large platelets and therefore a possible macrothrombocytopenia diagnosis could easily be inadvertently missed in clinical practice due to variable instrument settings. These findings suggest that ABCG5 heterozygosity may cause macrothrombocytopenia, that Ezetimibe treatment may resolve macrothrombocytopenia in such individuals, and that increased attention to platelet size on complete blood counts can aid in the identification of candidates for ABCG5 genetic testing who might benefit from Ezetimibe treatment.

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Molecular basis of cholesterol efflux via ABCG subfamily transporters

Cited by 55 publications

References 48 publications

Evolutionary origin and sequence signatures of the heterodimeric ABCG5/ABCG8 transporter

Evolutionary origin and sequence signatures of the heterodimeric ABCG5/ABCG8 transporter

Targeting Protein Translation in Melanoma by Inhibiting EEF-2 Kinase Regulates Cholesterol Metabolism though SREBP2 to Inhibit Tumour Development

Remediation of ABCG5-Linked Macrothrombocytopenia With Ezetimibe Therapy

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