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3.A.1.204.5
The ABCG5 (sterolin-1)/ABCG8 (sterolin-2) heterodimeric neutral sterol (cholesterol and plant sterols) (e.g., sitosterol and lutein) (phosphoryl donors ATP > CTP > GTP > UTP) exporter; present in the apical membranes of enterocytes and hepatocytes ((Reboul 2013). Cholesteryl oleate, phosphatidyl choline and enantiomeric cholesterol are poorly transported (mutation of either ABCG5 or ABCG8 cause sitosterolemia and coronary atherosclerosis) (Zhang et al., 2006; Wang et al., 2006; 2011). It is involved in cell signalling, creation of membrane asymmetry and apoptosis (Quazi and Molday, 2011). The ABCG5/ABCG8 heterodimer (G5G8) mediates excretion of neutral sterols as well as the drug, Marinobufagenin, a Na+/K+-ATPase inhibitor, in the liver and intestine (Lan et al. 2018). Mutations disrupting G5G8 cause sitosterolaemia, a disorder characterized by sterol accumulation and premature atherosclerosis. Lee et al. 2016 used crystallization in lipid bilayers to determine the X-ray structure in a nucleotide-free state at 3.9 Å resolution. The structure revealed a new transmembrane fold that is present in a large and functionally diverse superfamily of ABC transporters. The transmembrane domains are coupled to the nucleotide-binding sites by networks of interactions that differ between the active and inactive ATPases, reflecting the catalytic asymmetry of the transporter (Lee et al. 2016). High expression levels of both ABCG5 and ABCG8 were observed in liver, the digestive tract and the mammary gland. The system plays roles in lipid and sterol intestinal absorption, biliary excretion, and lipid trafficking and excretion during lactation (Viturro et al. 2006). ABCG5/G8 is active in the excretion of cholesterol and sterols into bile (vanBerge-Henegouwen et al. 2004). Disruption of the unique ABCG-family NBD:NBD interface impacts both drug transport and ATP hydrolysis (Kapoor et al. 2020). Transmembrane polar relay drives the allosteric regulation for the ABCG5/G8 sterol transporter (Xavier et al. 2020). Rare mutations can give rise to tendon xanthoma along with tendosynovitis (Wadsack et al. 2018). ABCG5/8 mediates secretion of neutral sterols into bile and the gut lumen, whereas G1 (TC# 3.A.1.204.12) transports cholesterol from macrophages to high-density lipoproteins (HDLs). Cryo-EM structures of human G5G8 in sterol-bound and human G1 in cholesterol- and ATP-bound states have been solved. Both transporters have a sterol-binding site that is accessible from the cytosolic leaflet. A second site is present midway through the transmembrane domains of ABCG5/G8. The Walker A motif of G8 adopts a unique conformation that accounts for the marked asymmetry in ATPase activities between the two nucleotide-binding sites of G5G8 (Sun et al. 2021). Residues have been mapped to the structural cores of TMSs), 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 (Pei and Cong 2022). Structural analysis of cholesterol binding and sterol selectivity by ABCG5/G8 have been reported (Farhat et al. 2022). ABCG5/G8 gene region variants exert differential effects on lipid profiles, blood pressure status, and gallstone disease history (Teng et al. 2023). Sitosterolemia is a rare inherited disorder caused by mutations in the ABCG5/ABCG8 genes. These genes encode proteins involved in the transport of plant sterols. Mutations in these genes lead to decreased excretion of phytosterols, which can accumulate in the body and lead to a variety of health problems, including premature coronary artery disease (Alenbawi et al. 2024). Maternal high-fat diet regulates offspring hepatic ABCG5 expression and cholesterol metabolism via the gut microbiota and its derived butyrate (Zhang et al. 2024). Specifically, maternal high-fat diet feeding inhibits hepatic cholesterol excretion and down-regulates ABCG5 through the butyrate-AMPK-pHDAC5 pathway in offspring at weaning.

Accession Number:Q9H222
Protein Name:ABCG5 aka ATP-binding cassette sub-family G member 5
Length:651
Molecular Weight:72504.00
Species:Homo sapiens (Human) [9606]
Number of TMSs:7
Location1 / Topology2 / Orientation3: Membrane1 / Multi-pass membrane protein2
Substrate 1,2-diacyl-sn-glycero-3-phosphocholine(1+), cholesteryl oleate, cholesterol, sterol, lutein, drug

Cross database links:

RefSeq: NP_071881.1   
Entrez Gene ID: 64240   
Pfam: PF01061    PF00005   
OMIM: 210250  phenotype
605459  gene
KEGG: hsa:64240   

Gene Ontology

GO:0016324 C:apical plasma membrane
GO:0016021 C:integral to membrane
GO:0005524 F:ATP binding
GO:0016887 F:ATPase activity
GO:0046982 F:protein heterodimerization activity
GO:0033344 P:cholesterol efflux
GO:0042632 P:cholesterol homeostasis
GO:0007588 P:excretion
GO:0030299 P:intestinal cholesterol absorption
GO:0045796 P:negative regulation of intestinal cholester...
GO:0010949 P:negative regulation of intestinal phytoster...

References (5)

[1] “Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters.”  Berge K.E.et.al.   11099417
[2] “Identification of a gene, ABCG5, important in the regulation of dietary cholesterol absorption.”  Lee M.-H.et.al.   11138003
[3] “Role of ABCG1 and other ABCG family members in lipid metabolism.”  Schmitz G.et.al.   11590207
[4] “Two genes that map to the STSL locus cause sitosterolemia: genomic structure and spectrum of mutations involving sterolin-1 and sterolin-2, encoded by ABCG5 and ABCG8, respectively.”  Lu K.et.al.   11452359
[5] “Mutations in ATP-cassette binding proteins G5 (ABCG5) and G8 (ABCG8) causing sitosterolemia.”  Hubacek J.A.et.al.   11668628
Structure:
5do7     

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Predict TMSs (Predict number of transmembrane segments)
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FASTA formatted sequence
1:	MGDLSSLTPG GSMGLQVNRG SQSSLEGAPA TAPEPHSLGI LHASYSVSHR VRPWWDITSC 
61:	RQQWTRQILK DVSLYVESGQ IMCILGSSGS GKTTLLDAMS GRLGRAGTFL GEVYVNGRAL 
121:	RREQFQDCFS YVLQSDTLLS SLTVRETLHY TALLAIRRGN PGSFQKKVEA VMAELSLSHV 
181:	ADRLIGNYSL GGISTGERRR VSIAAQLLQD PKVMLFDEPT TGLDCMTANQ IVVLLVELAR 
241:	RNRIVVLTIH QPRSELFQLF DKIAILSFGE LIFCGTPAEM LDFFNDCGYP CPEHSNPFDF 
301:	YMDLTSVDTQ SKEREIETSK RVQMIESAYK KSAICHKTLK NIERMKHLKT LPMVPFKTKD 
361:	SPGVFSKLGV LLRRVTRNLV RNKLAVITRL LQNLIMGLFL LFFVLRVRSN VLKGAIQDRV 
421:	GLLYQFVGAT PYTGMLNAVN LFPVLRAVSD QESQDGLYQK WQMMLAYALH VLPFSVVATM 
481:	IFSSVCYWTL GLHPEVARFG YFSAALLAPH LIGEFLTLVL LGIVQNPNIV NSVVALLSIA 
541:	GVLVGSGFLR NIQEMPIPFK IISYFTFQKY CSEILVVNEF YGLNFTCGSS NVSVTTNPMC 
601:	AFTQGIQFIE KTCPGATSRF TMNFLILYSF IPALVILGIV VFKIRDHLIS R