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3.A.1.211.14
cAMP-dependent and sulfonylurea-sensitive anion transporter, ABCA1 (ABCAI) of 2261 aas. It is a key gatekeeper catalyzing intracellular phospholipid and cholesterol transport (Orlowski et al. 2007).  It interacts with the MEGF10 protein and is 95% identical to the mouse orthologue, 3.A.1.211.1.  Cholesterol efflux from THP-1 macrophages decreases in the presence of plasma obtained from humans and rats with mild hyperbilirubinemia. A direct effect of unconjugated bilirubin on cholesterol efflux was demonstrated and is associated with decreased ABCA1 protein expression (Wang et al. 2017). A cryoEM structure (4.1 Å) revealed that the two transmembrane domains contact each other through a narrow interface in the intracellular leaflet of the membrane, and two extracellular domains of ABCA1 enclose an elongated hydrophobic tunnel. Structural mapping of dozens of disease-related mutations allowed potential interpretation of their diverse pathogenic mechanisms. Structure-based analyses suggested a plausible "lateral access" mechanism for ABCA1-mediated lipid export that may be distinct from the conventional alternating-access paradigm. ABCA1 acts in concert with ABCB1, ABCG2 and ABCG4 to efflux amyloid-β peptide (Aβ) from the brain across the blood-brain barrier (BBB) (Kuai et al. 2018). One substrate of systems ABCA1, ABCB1 and ABCC1 is arsenate, where ABCC1 is most effective while ABCA1 and ABCB1 are less effective (Zhou et al. 2018). ABCA1 transports lipids and cholesterol to apolipoprotein E (APOE) (Castranio et al. 2018). Cholesterol binding to ABCA1 may interfere with ATP binding in both nucleotide-binding domains of the ABCA1 structure (Dergunov et al. 2018).  Adiponectin, possibly acting through AdipoR1 and AdipoR2, plays a key role in promoting ABCA1-dependent cholesterol efflux (Hafiane et al. 2019). Reverse cholesterol transport or cholesterol efflux is part of an extensive plasma membranes remodelling process in spermatozoa that induces hyperactivated motility and is imperative for fertilization. Cholesterol efflux depends on high density lipoproteins (HDLs) that interact with transmembrane cholesterol transporters, such as ABCA1 and scavenger receptor class B, type I (SR-BI; TC# 9.B.39.1.3) (Bernecic et al. 2021). Smoking can influence the expression of the ABCA1 gene, thereby modulating lipid transport processes in macrophages, which are part of the mechanisms of inflammation development (Kotlyarov and Kotlyarova 2021). The cavity enclosed within the ATP-unbound form of ABCA1 is narrow at the distal ends of the TMD as well as the ECD region, substantiating the "lateral access" theory (Sunidhi et al. 2021). Curcumin ameliorates lipid metabolic disorder and cognitive dysfunction via ABCA1 (Tian et al. 2021). Insulin downregulates the expression of ABC A-I in human hepatoma cell line HepG2 in a FOXO1 and LXR-dependent manner (Shavva et al. 2022). Loss of function of the ABCA1 gene results in low levels of HDL as well as a concomitant reduction in plasma HexCer levels (Iqbal et al. 2022). Inflammation and immunomodulatory therapies influence the relationship between the ABCA1 transporter-mediated cholesterol efflux capacity and coronary atherosclerosis in rheumatoid arthritis (Karpouzas et al. 2023). Macrophage cholesterol efflux is mediated by ABCA1 and constitutes the initial and rate-limiting step of reverse cholesterol transport, displaying a negative correlation with the development of atherosclerosis.  Macrophage allosterically activate AMPK (see TC# 8.A.104) to enhance ABCA1 stability by retarding the calpain-mediated degradation pathway (Li et al. 2023).

Accession Number:O95477
Protein Name:ATP-binding cassette sub-family A member 1
Length:2261
Molecular Weight:254302.00
Species:Homo sapiens (Human) [9606]
Number of TMSs:15
Location1 / Topology2 / Orientation3: Membrane1 / Multi-pass membrane protein2
Substrate anion, phospholipid, amyloid-beta, cholesterol

Cross database links:

Structure:
5XJY     

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Predict TMSs (Predict number of transmembrane segments)
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FASTA formatted sequence
1:	MACWPQLRLL LWKNLTFRRR QTCQLLLEVA WPLFIFLILI SVRLSYPPYE QHECHFPNKA 
61:	MPSAGTLPWV QGIICNANNP CFRYPTPGEA PGVVGNFNKS IVARLFSDAR RLLLYSQKDT 
121:	SMKDMRKVLR TLQQIKKSSS NLKLQDFLVD NETFSGFLYH NLSLPKSTVD KMLRADVILH 
181:	KVFLQGYQLH LTSLCNGSKS EEMIQLGDQE VSELCGLPRE KLAAAERVLR SNMDILKPIL 
241:	RTLNSTSPFP SKELAEATKT LLHSLGTLAQ ELFSMRSWSD MRQEVMFLTN VNSSSSSTQI 
301:	YQAVSRIVCG HPEGGGLKIK SLNWYEDNNY KALFGGNGTE EDAETFYDNS TTPYCNDLMK 
361:	NLESSPLSRI IWKALKPLLV GKILYTPDTP ATRQVMAEVN KTFQELAVFH DLEGMWEELS 
421:	PKIWTFMENS QEMDLVRMLL DSRDNDHFWE QQLDGLDWTA QDIVAFLAKH PEDVQSSNGS 
481:	VYTWREAFNE TNQAIRTISR FMECVNLNKL EPIATEVWLI NKSMELLDER KFWAGIVFTG 
541:	ITPGSIELPH HVKYKIRMDI DNVERTNKIK DGYWDPGPRA DPFEDMRYVW GGFAYLQDVV 
601:	EQAIIRVLTG TEKKTGVYMQ QMPYPCYVDD IFLRVMSRSM PLFMTLAWIY SVAVIIKGIV 
661:	YEKEARLKET MRIMGLDNSI LWFSWFISSL IPLLVSAGLL VVILKLGNLL PYSDPSVVFV 
721:	FLSVFAVVTI LQCFLISTLF SRANLAAACG GIIYFTLYLP YVLCVAWQDY VGFTLKIFAS 
781:	LLSPVAFGFG CEYFALFEEQ GIGVQWDNLF ESPVEEDGFN LTTSVSMMLF DTFLYGVMTW 
841:	YIEAVFPGQY GIPRPWYFPC TKSYWFGEES DEKSHPGSNQ KRISEICMEE EPTHLKLGVS 
901:	IQNLVKVYRD GMKVAVDGLA LNFYEGQITS FLGHNGAGKT TTMSILTGLF PPTSGTAYIL 
961:	GKDIRSEMST IRQNLGVCPQ HNVLFDMLTV EEHIWFYARL KGLSEKHVKA EMEQMALDVG 
1021:	LPSSKLKSKT SQLSGGMQRK LSVALAFVGG SKVVILDEPT AGVDPYSRRG IWELLLKYRQ 
1081:	GRTIILSTHH MDEADVLGDR IAIISHGKLC CVGSSLFLKN QLGTGYYLTL VKKDVESSLS 
1141:	SCRNSSSTVS YLKKEDSVSQ SSSDAGLGSD HESDTLTIDV SAISNLIRKH VSEARLVEDI 
1201:	GHELTYVLPY EAAKEGAFVE LFHEIDDRLS DLGISSYGIS ETTLEEIFLK VAEESGVDAE 
1261:	TSDGTLPARR NRRAFGDKQS CLRPFTEDDA ADPNDSDIDP ESRETDLLSG MDGKGSYQVK 
1321:	GWKLTQQQFV ALLWKRLLIA RRSRKGFFAQ IVLPAVFVCI ALVFSLIVPP FGKYPSLELQ 
1381:	PWMYNEQYTF VSNDAPEDTG TLELLNALTK DPGFGTRCME GNPIPDTPCQ AGEEEWTTAP 
1441:	VPQTIMDLFQ NGNWTMQNPS PACQCSSDKI KKMLPVCPPG AGGLPPPQRK QNTADILQDL 
1501:	TGRNISDYLV KTYVQIIAKS LKNKIWVNEF RYGGFSLGVS NTQALPPSQE VNDAIKQMKK 
1561:	HLKLAKDSSA DRFLNSLGRF MTGLDTKNNV KVWFNNKGWH AISSFLNVIN NAILRANLQK 
1621:	GENPSHYGIT AFNHPLNLTK QQLSEVALMT TSVDVLVSIC VIFAMSFVPA SFVVFLIQER 
1681:	VSKAKHLQFI SGVKPVIYWL SNFVWDMCNY VVPATLVIII FICFQQKSYV SSTNLPVLAL 
1741:	LLLLYGWSIT PLMYPASFVF KIPSTAYVVL TSVNLFIGIN GSVATFVLEL FTDNKLNNIN 
1801:	DILKSVFLIF PHFCLGRGLI DMVKNQAMAD ALERFGENRF VSPLSWDLVG RNLFAMAVEG 
1861:	VVFFLITVLI QYRFFIRPRP VNAKLSPLND EDEDVRRERQ RILDGGGQND ILEIKELTKI 
1921:	YRRKRKPAVD RICVGIPPGE CFGLLGVNGA GKSSTFKMLT GDTTVTRGDA FLNKNSILSN 
1981:	IHEVHQNMGY CPQFDAITEL LTGREHVEFF ALLRGVPEKE VGKVGEWAIR KLGLVKYGEK 
2041:	YAGNYSGGNK RKLSTAMALI GGPPVVFLDE PTTGMDPKAR RFLWNCALSV VKEGRSVVLT 
2101:	SHSMEECEAL CTRMAIMVNG RFRCLGSVQH LKNRFGDGYT IVVRIAGSNP DLKPVQDFFG 
2161:	LAFPGSVLKE KHRNMLQYQL PSSLSSLARI FSILSQSKKR LHIEDYSVSQ TTLDQVFVNF 
2221:	AKDQSDDDHL KDLSLHKNQT VVDVAVLTSF LQDEKVKESY V