MDR4_ASPFU
ID MDR4_ASPFU Reviewed; 1330 AA.
AC Q4WSI1;
DT 10-OCT-2018, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2005, sequence version 1.
DT 03-AUG-2022, entry version 126.
DE RecName: Full=ABC multidrug transporter mdr4 {ECO:0000303|PubMed:12709346};
GN Name=mdr4 {ECO:0000303|PubMed:12709346}; ORFNames=AFUA_1G12690;
OS Neosartorya fumigata (strain ATCC MYA-4609 / Af293 / CBS 101355 / FGSC
OS A1100) (Aspergillus fumigatus).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Aspergillus;
OC Aspergillus subgen. Fumigati.
OX NCBI_TaxID=330879;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=ATCC MYA-4609 / Af293 / CBS 101355 / FGSC A1100;
RX PubMed=16372009; DOI=10.1038/nature04332;
RA Nierman W.C., Pain A., Anderson M.J., Wortman J.R., Kim H.S., Arroyo J.,
RA Berriman M., Abe K., Archer D.B., Bermejo C., Bennett J.W., Bowyer P.,
RA Chen D., Collins M., Coulsen R., Davies R., Dyer P.S., Farman M.L.,
RA Fedorova N., Fedorova N.D., Feldblyum T.V., Fischer R., Fosker N.,
RA Fraser A., Garcia J.L., Garcia M.J., Goble A., Goldman G.H., Gomi K.,
RA Griffith-Jones S., Gwilliam R., Haas B.J., Haas H., Harris D.E.,
RA Horiuchi H., Huang J., Humphray S., Jimenez J., Keller N., Khouri H.,
RA Kitamoto K., Kobayashi T., Konzack S., Kulkarni R., Kumagai T., Lafton A.,
RA Latge J.-P., Li W., Lord A., Lu C., Majoros W.H., May G.S., Miller B.L.,
RA Mohamoud Y., Molina M., Monod M., Mouyna I., Mulligan S., Murphy L.D.,
RA O'Neil S., Paulsen I., Penalva M.A., Pertea M., Price C., Pritchard B.L.,
RA Quail M.A., Rabbinowitsch E., Rawlins N., Rajandream M.A., Reichard U.,
RA Renauld H., Robson G.D., Rodriguez de Cordoba S., Rodriguez-Pena J.M.,
RA Ronning C.M., Rutter S., Salzberg S.L., Sanchez M., Sanchez-Ferrero J.C.,
RA Saunders D., Seeger K., Squares R., Squares S., Takeuchi M., Tekaia F.,
RA Turner G., Vazquez de Aldana C.R., Weidman J., White O., Woodward J.R.,
RA Yu J.-H., Fraser C.M., Galagan J.E., Asai K., Machida M., Hall N.,
RA Barrell B.G., Denning D.W.;
RT "Genomic sequence of the pathogenic and allergenic filamentous fungus
RT Aspergillus fumigatus.";
RL Nature 438:1151-1156(2005).
RN [2]
RP INDUCTION, AND FUNCTION.
RX PubMed=12709346; DOI=10.1128/aac.47.5.1719-1726.2003;
RA Nascimento A.M., Goldman G.H., Park S., Marras S.A., Delmas G., Oza U.,
RA Lolans K., Dudley M.N., Mann P.A., Perlin D.S.;
RT "Multiple resistance mechanisms among Aspergillus fumigatus mutants with
RT high-level resistance to itraconazole.";
RL Antimicrob. Agents Chemother. 47:1719-1726(2003).
RN [3]
RP INDUCTION.
RX PubMed=15504870; DOI=10.1128/aac.48.11.4405-4413.2004;
RA da Silva Ferreira M.E., Capellaro J.L., dos Reis Marques E., Malavazi I.,
RA Perlin D., Park S., Anderson J.B., Colombo A.L., Arthington-Skaggs B.A.,
RA Goldman M.H., Goldman G.H.;
RT "In vitro evolution of itraconazole resistance in Aspergillus fumigatus
RT involves multiple mechanisms of resistance.";
RL Antimicrob. Agents Chemother. 48:4405-4413(2004).
RN [4]
RP INDUCTION.
RX PubMed=18721228; DOI=10.1111/j.1365-2958.2008.06376.x;
RA Schrettl M., Kim H.S., Eisendle M., Kragl C., Nierman W.C., Heinekamp T.,
RA Werner E.R., Jacobsen I., Illmer P., Yi H., Brakhage A.A., Haas H.;
RT "SreA-mediated iron regulation in Aspergillus fumigatus.";
RL Mol. Microbiol. 70:27-43(2008).
RN [5]
RP FUNCTION, AND INDUCTION.
RX PubMed=21321135; DOI=10.1128/aac.01189-10;
RA Rajendran R., Mowat E., McCulloch E., Lappin D.F., Jones B., Lang S.,
RA Majithiya J.B., Warn P., Williams C., Ramage G.;
RT "Azole resistance of Aspergillus fumigatus biofilms is partly associated
RT with efflux pump activity.";
RL Antimicrob. Agents Chemother. 55:2092-2097(2011).
RN [6]
RP INDUCTION.
RX PubMed=21724936; DOI=10.1128/ec.05102-11;
RA Gibbons J.G., Beauvais A., Beau R., McGary K.L., Latge J.P., Rokas A.;
RT "Global transcriptome changes underlying colony growth in the opportunistic
RT human pathogen Aspergillus fumigatus.";
RL Eukaryot. Cell 11:68-78(2012).
RN [7]
RP INDUCTION.
RX PubMed=28080217; DOI=10.1089/mdr.2016.0217;
RA Li S.X., Song Y.J., Jiang L., Zhao Y.J., Guo H., Li D.M., Zhu K.J.,
RA Zhang H.;
RT "Synergistic effects of tetrandrine with posaconazole against Aspergillus
RT fumigatus.";
RL Microb. Drug Resist. 23:674-681(2017).
CC -!- FUNCTION: Pleiotropic ABC efflux transporter that confers resistance to
CC azoles such as itraconazole and voriconazole.
CC {ECO:0000269|PubMed:12709346, ECO:0000269|PubMed:21321135}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + H2O + itraconazole(in) = ADP + H(+) + itraconazole(out)
CC + phosphate; Xref=Rhea:RHEA:33503, ChEBI:CHEBI:6076,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:43474, ChEBI:CHEBI:456216;
CC Evidence={ECO:0000305|PubMed:12709346};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:33504;
CC Evidence={ECO:0000305|PubMed:12709346};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + H2O + voriconazole(in) = ADP + H(+) + phosphate +
CC voriconazole(out); Xref=Rhea:RHEA:61912, ChEBI:CHEBI:10023,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:43474, ChEBI:CHEBI:456216;
CC Evidence={ECO:0000305|PubMed:21321135};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:61913;
CC Evidence={ECO:0000305|PubMed:21321135};
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000305}; Multi-pass membrane
CC protein {ECO:0000255}.
CC -!- INDUCTION: Expression is induced by voriconazole exposure in vitro and
CC in mice (PubMed:21321135). Expression is increased in clinical azole-
CC resistant isolates and by the presence of itraconazole
CC (PubMed:12709346, PubMed:15504870). Expression is also up-regulated
CC during biofilm growth (PubMed:21724936). Expression is repressed by
CC iron in an SreA-dependent manner (PubMed:18721228). Expression is down-
CC regulated by tetrandrine and posaconazole in a synergistic manner
CC (PubMed:28080217). {ECO:0000269|PubMed:12709346,
CC ECO:0000269|PubMed:15504870, ECO:0000269|PubMed:18721228,
CC ECO:0000269|PubMed:21321135, ECO:0000269|PubMed:21724936,
CC ECO:0000269|PubMed:28080217}.
CC -!- SIMILARITY: Belongs to the ABC transporter superfamily. ABCB family.
CC Multidrug resistance exporter (TC 3.A.1.201) subfamily. {ECO:0000305}.
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DR EMBL; AAHF01000004; EAL90601.1; -; Genomic_DNA.
DR RefSeq; XP_752639.1; XM_747546.1.
DR AlphaFoldDB; Q4WSI1; -.
DR SMR; Q4WSI1; -.
DR EnsemblFungi; EAL90601; EAL90601; AFUA_1G12690.
DR GeneID; 3510389; -.
DR KEGG; afm:AFUA_1G12690; -.
DR VEuPathDB; FungiDB:Afu1g12690; -.
DR eggNOG; KOG0055; Eukaryota.
DR HOGENOM; CLU_000604_17_8_1; -.
DR InParanoid; Q4WSI1; -.
DR OMA; HRLNTIH; -.
DR OrthoDB; 186078at2759; -.
DR Proteomes; UP000002530; Chromosome 1.
DR GO; GO:0016021; C:integral component of membrane; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0140359; F:ABC-type transporter activity; IEA:InterPro.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0042626; F:ATPase-coupled transmembrane transporter activity; IBA:GO_Central.
DR GO; GO:0055085; P:transmembrane transport; IBA:GO_Central.
DR Gene3D; 1.20.1560.10; -; 2.
DR Gene3D; 3.40.50.300; -; 2.
DR InterPro; IPR003593; AAA+_ATPase.
DR InterPro; IPR011527; ABC1_TM_dom.
DR InterPro; IPR036640; ABC1_TM_sf.
DR InterPro; IPR003439; ABC_transporter-like_ATP-bd.
DR InterPro; IPR017871; ABC_transporter-like_CS.
DR InterPro; IPR027417; P-loop_NTPase.
DR InterPro; IPR039421; Type_1_exporter.
DR PANTHER; PTHR24221; PTHR24221; 2.
DR Pfam; PF00664; ABC_membrane; 2.
DR Pfam; PF00005; ABC_tran; 2.
DR SMART; SM00382; AAA; 2.
DR SUPFAM; SSF52540; SSF52540; 2.
DR SUPFAM; SSF90123; SSF90123; 2.
DR PROSITE; PS50929; ABC_TM1F; 2.
DR PROSITE; PS00211; ABC_TRANSPORTER_1; 2.
DR PROSITE; PS50893; ABC_TRANSPORTER_2; 2.
PE 2: Evidence at transcript level;
KW ATP-binding; Cell membrane; Glycoprotein; Membrane; Nucleotide-binding;
KW Reference proteome; Repeat; Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1..1330
FT /note="ABC multidrug transporter mdr4"
FT /id="PRO_0000445104"
FT TRANSMEM 90..110
FT /note="Helical"
FT /evidence="ECO:0000255, ECO:0000255|PROSITE-
FT ProRule:PRU00441"
FT TRANSMEM 144..164
FT /note="Helical"
FT /evidence="ECO:0000255, ECO:0000255|PROSITE-
FT ProRule:PRU00441"
FT TRANSMEM 218..238
FT /note="Helical"
FT /evidence="ECO:0000255, ECO:0000255|PROSITE-
FT ProRule:PRU00441"
FT TRANSMEM 243..263
FT /note="Helical"
FT /evidence="ECO:0000255, ECO:0000255|PROSITE-
FT ProRule:PRU00441"
FT TRANSMEM 324..344
FT /note="Helical"
FT /evidence="ECO:0000255, ECO:0000255|PROSITE-
FT ProRule:PRU00441"
FT TRANSMEM 370..390
FT /note="Helical"
FT /evidence="ECO:0000255, ECO:0000255|PROSITE-
FT ProRule:PRU00441"
FT TRANSMEM 761..781
FT /note="Helical"
FT /evidence="ECO:0000255, ECO:0000255|PROSITE-
FT ProRule:PRU00441"
FT TRANSMEM 806..826
FT /note="Helical"
FT /evidence="ECO:0000255, ECO:0000255|PROSITE-
FT ProRule:PRU00441"
FT TRANSMEM 871..893
FT /note="Helical"
FT /evidence="ECO:0000255, ECO:0000255|PROSITE-
FT ProRule:PRU00441"
FT TRANSMEM 903..923
FT /note="Helical"
FT /evidence="ECO:0000255, ECO:0000255|PROSITE-
FT ProRule:PRU00441"
FT TRANSMEM 989..1009
FT /note="Helical"
FT /evidence="ECO:0000255, ECO:0000255|PROSITE-
FT ProRule:PRU00441"
FT TRANSMEM 1023..1043
FT /note="Helical"
FT /evidence="ECO:0000255, ECO:0000255|PROSITE-
FT ProRule:PRU00441"
FT DOMAIN 94..392
FT /note="ABC transmembrane type-1 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT DOMAIN 428..666
FT /note="ABC transporter 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00434"
FT DOMAIN 761..1049
FT /note="ABC transmembrane type-1 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT DOMAIN 1086..1325
FT /note="ABC transporter 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00434"
FT REGION 717..736
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 719..736
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 463..470
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00434"
FT BINDING 1121..1128
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00434"
FT CARBOHYD 3
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 707
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ SEQUENCE 1330 AA; 144723 MW; 0E3C71FDF7A80370 CRC64;
MQNTTVHGLY FCHPTSIDGN PELLAVSRRS LSRGDHVTFT ASQCRPKRLQ CCQWHSCTIS
STHIPTKDDL GKSFAYLRLL FSLDYTIADV LLIIGGLLFA ICAGIPFPLL GIVFGDLIND
LNTVTCSSSD RATADLSSAV RAKVLYVIYI TIANFCFIYA HSTCWCLVSE RLARRYRRRY
FESIIKQEAK FIESLPSGDV VSRLVSDIEL VQSGTSEKVG LVISTLSYFV AAYVVAFIKV
PKIAGMLVSV VPCFFLMALG GGHYIKKFAG RLAEKVNAAT SIASSSLSHL TLVHAFNAND
RLEKRFAGYL LQSRKDAVRK ATTHAAQLGC LYFIAYSANA LAFWEGSQMI SKSVADGNSG
TSVGAVYTVI FVLIDASFIL SQVAPFIHVF ASAAGASERL LQVINRPSAI DGTSDSGDKT
AAFGEEDIRF RDVHFKYPSR PDVPVLQGVT FNIPPKKHTA IVGPSGGGKS TVVALLERFY
DPDSGDVLIG DKNFRDINVR YLRGNIGYVQ QEPSLLDRTI LENIAYGLVC VTEIVDLVKE
AAANANALGF IEALPYGFAT NVGTAGNQLS GGQKQRIALA RALVREPCLL ILDEATAALD
STSEQLIQAA LNRVSERVTT VSIAHRLATA KNAHKIVVVQ SGRVTEEGSH TDLVSRGGVY
AEMVRLQNLG KLSLDDRVIS GDMISALNAT PETRQLLDEK QAFVDGNRSD ITEDTVVADT
PSDSRDGSEE EARKKRKRTR SAGFVTRYTF ALIRPNLHWV LLGLAMSVII GGSYSAEAIV
FGHTVGSLSP CRSAEAISRD GNLYGLLFFI LALVEFGANV VGGCAFGWAA DKVLYRIRVL
SLRSLLGQTV KWHESEDRTP GTLLTYITGD ASALGGITGT TIGLLLATAV NLIGGLVISF
SIAWKITIVL FPTIPVLLVS GMMKLRVQKQ LAERHQKAFA KATAVTIEAV DNIRAVSAFS
LEKQSYQVYG RALRGPYRAT IKATFHGNAW LALAFSISNL VYALAYWWGS KQIAEGRYSQ
TQFFIVMPAL LFSTQSCGQM FALAPDISKA GVASSNIVEL LTTRSAEDEV TPGSSHSFQP
SSSMGAQLRD VHFTYPHRPE RPVLKGLNID IKPGQFCALV GPSGSGKSTT FAMLERFYRP
NAGAVVIDGV DVTRQVGTEF RDDIALVPQQ NILFEGTVAF NVALGACPGH EPTQEEIEEA
CRMANIHDVI MTLPQGYQTM CSHDGKQFSG GQRQRLSIAR ALVRKPRLLL LDESTSALDV
ESEKRIQEAL ATLAGRTTVV AIAHRLNTIH RADQIFLIED GRCIEQGTHQ QLIQRSETYR
TSVIHQSLET
