AFR1_CRYNH
ID AFR1_CRYNH Reviewed; 1543 AA.
AC J9VME1;
DT 02-JUN-2021, integrated into UniProtKB/Swiss-Prot.
DT 28-NOV-2012, sequence version 1.
DT 03-AUG-2022, entry version 52.
DE RecName: Full=ABC multidrug transporter AFR1 {ECO:0000303|PubMed:25630649};
GN Name=AFR1 {ECO:0000303|PubMed:25630649}; ORFNames=CNAG_00730;
OS Cryptococcus neoformans var. grubii serotype A (strain H99 / ATCC 208821 /
OS CBS 10515 / FGSC 9487) (Filobasidiella neoformans var. grubii).
OC Eukaryota; Fungi; Dikarya; Basidiomycota; Agaricomycotina; Tremellomycetes;
OC Tremellales; Cryptococcaceae; Cryptococcus;
OC Cryptococcus neoformans species complex.
OX NCBI_TaxID=235443;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=H99 / ATCC 208821 / CBS 10515 / FGSC 9487;
RX PubMed=24743168; DOI=10.1371/journal.pgen.1004261;
RA Janbon G., Ormerod K.L., Paulet D., Byrnes E.J. III, Yadav V.,
RA Chatterjee G., Mullapudi N., Hon C.-C., Billmyre R.B., Brunel F.,
RA Bahn Y.-S., Chen W., Chen Y., Chow E.W.L., Coppee J.-Y., Floyd-Averette A.,
RA Gaillardin C., Gerik K.J., Goldberg J., Gonzalez-Hilarion S., Gujja S.,
RA Hamlin J.L., Hsueh Y.-P., Ianiri G., Jones S., Kodira C.D., Kozubowski L.,
RA Lam W., Marra M., Mesner L.D., Mieczkowski P.A., Moyrand F., Nielsen K.,
RA Proux C., Rossignol T., Schein J.E., Sun S., Wollschlaeger C., Wood I.A.,
RA Zeng Q., Neuveglise C., Newlon C.S., Perfect J.R., Lodge J.K., Idnurm A.,
RA Stajich J.E., Kronstad J.W., Sanyal K., Heitman J., Fraser J.A.,
RA Cuomo C.A., Dietrich F.S.;
RT "Analysis of the genome and transcriptome of Cryptococcus neoformans var.
RT grubii reveals complex RNA expression and microevolution leading to
RT virulence attenuation.";
RL PLoS Genet. 10:E1004261-E1004261(2014).
RN [2]
RP FUNCTION, CATALYTIC ACTIVITY, SUBSTRATE SPECIFICITY, BIOPHYSICOCHEMICAL
RP PROPERTIES, AND SUBCELLULAR LOCATION.
RX PubMed=25630649; DOI=10.1093/jac/dku554;
RA Basso L.R. Jr., Gast C.E., Bruzual I., Wong B.;
RT "Identification and properties of plasma membrane azole efflux pumps from
RT the pathogenic fungi Cryptococcus gattii and Cryptococcus neoformans.";
RL J. Antimicrob. Chemother. 70:1396-1407(2015).
RN [3]
RP FUNCTION, DISRUPTION PHENOTYPE, AND INDUCTION.
RX PubMed=29378705; DOI=10.1128/aac.01751-17;
RA Chang M., Sionov E., Khanal Lamichhane A., Kwon-Chung K.J., Chang Y.C.;
RT "Roles of three Cryptococcus neoformans and Cryptococcus gattii efflux
RT pump-coding genes in response to drug treatment.";
RL Antimicrob. Agents Chemother. 62:0-0(2018).
CC -!- FUNCTION: Major pleiotropic ABC efflux transporter that confers
CC resistance to structurally and functionally unrelated compounds
CC including azoles such as fluconazole (FLC), itraconazole (ITC),
CC posaconazole (POS), and voriconazole (VRC) (PubMed:25630649,
CC PubMed:29378705). Is also able to efflux the eukaryote protein
CC synthesis inhibitor cycloheximide (CHX) (PubMed:29378705).
CC {ECO:0000269|PubMed:25630649, ECO:0000269|PubMed:29378705}.
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:0000269|PubMed:25630649};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:33504;
CC Evidence={ECO:0000269|PubMed:25630649};
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:0000269|PubMed:25630649};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:61913;
CC Evidence={ECO:0000269|PubMed:25630649};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + fluconazole(in) + H2O = ADP + fluconazole(out) + H(+) +
CC phosphate; Xref=Rhea:RHEA:61916, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:43474,
CC ChEBI:CHEBI:46081, ChEBI:CHEBI:456216;
CC Evidence={ECO:0000269|PubMed:25630649};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:61917;
CC Evidence={ECO:0000269|PubMed:25630649};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=0.26 uM for fluconazole transport {ECO:0000269|PubMed:25630649};
CC Vmax=3.22 pmol/min/mg enzyme for fluconazole transport
CC {ECO:0000269|PubMed:25630649};
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:25630649};
CC Multi-pass membrane protein {ECO:0000255}.
CC -!- INDUCTION: Expression is induced in the presence of fluconazole (FLC).
CC {ECO:0000269|PubMed:29378705}.
CC -!- DISRUPTION PHENOTYPE: Results in drastically higher susceptibility to
CC fluconazole (FLC), itraconazole (ITC), voriconazole (VRC), as well as
CC to the eukaryote protein synthesis inhibitor cycloheximide (CHX).
CC {ECO:0000269|PubMed:29378705}.
CC -!- SIMILARITY: Belongs to the ABC transporter superfamily. ABCG family.
CC PDR (TC 3.A.1.205) subfamily. {ECO:0000305}.
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DR EMBL; CP003820; AFR92860.1; -; Genomic_DNA.
DR RefSeq; XP_012046918.1; XM_012191528.1.
DR AlphaFoldDB; J9VME1; -.
DR SMR; J9VME1; -.
DR EnsemblFungi; AFR92860; AFR92860; CNAG_00730.
DR GeneID; 23884510; -.
DR VEuPathDB; FungiDB:CNAG_00730; -.
DR HOGENOM; CLU_000604_35_0_1; -.
DR Proteomes; UP000010091; Chromosome 1.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
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 CDD; cd03233; ABCG_PDR_domain1; 1.
DR CDD; cd03232; ABCG_PDR_domain2; 1.
DR Gene3D; 3.40.50.300; -; 2.
DR InterPro; IPR003593; AAA+_ATPase.
DR InterPro; IPR013525; ABC_2_trans.
DR InterPro; IPR029481; ABC_trans_N.
DR InterPro; IPR003439; ABC_transporter-like_ATP-bd.
DR InterPro; IPR017871; ABC_transporter-like_CS.
DR InterPro; IPR043926; ABCG_dom.
DR InterPro; IPR034001; ABCG_PDR_1.
DR InterPro; IPR034003; ABCG_PDR_2.
DR InterPro; IPR027417; P-loop_NTPase.
DR InterPro; IPR010929; PDR_CDR_ABC.
DR Pfam; PF01061; ABC2_membrane; 2.
DR Pfam; PF19055; ABC2_membrane_7; 1.
DR Pfam; PF00005; ABC_tran; 2.
DR Pfam; PF14510; ABC_trans_N; 1.
DR Pfam; PF06422; PDR_CDR; 1.
DR SMART; SM00382; AAA; 1.
DR SUPFAM; SSF52540; SSF52540; 2.
DR PROSITE; PS00211; ABC_TRANSPORTER_1; 1.
DR PROSITE; PS50893; ABC_TRANSPORTER_2; 2.
PE 1: Evidence at protein level;
KW ATP-binding; Cell membrane; Glycoprotein; Membrane; Nucleotide-binding;
KW Repeat; Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1..1543
FT /note="ABC multidrug transporter AFR1"
FT /id="PRO_0000452663"
FT TRANSMEM 585..605
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 619..639
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 670..690
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 695..715
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 727..747
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 845..865
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 1254..1274
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 1285..1305
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 1336..1356
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 1366..1386
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 1391..1411
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 1517..1537
FT /note="Helical"
FT /evidence="ECO:0000255"
FT DOMAIN 222..474
FT /note="ABC transporter 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00434"
FT DOMAIN 918..1160
FT /note="ABC transporter 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00434"
FT REGION 1..85
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 119..157
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 14..48
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 49..85
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 954..961
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00434"
FT CARBOHYD 117
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 208
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 398
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 823
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 1223
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ SEQUENCE 1543 AA; 172527 MW; 1C03EF1A9AB62C8E CRC64;
MSAAGVPAEL NNLGAPITAT TQNPSGLANS QVTSGPVSSA TQHDEHRSSA GNTLADEEDD
KAVEAEKAEA IDAAGDGKQK RLPADSSEDI VAELEPHHVS VHRGKEEFAA LERKYSNLSQ
RSQHELHRPT TRHSVRSSFS RKDRVVSRLT QDDAEKAKEG EGEFNLVEVL RSGRENQDEA
GIKRKAVGVV WEDHEVIGAG GMRINIRNFS SAIIEQFMMP AIKVLGIFGF NPFAPKPKAI
LHPSSGLLKP GEMCLVLGRP EAGCTTFLKT ITNQRAGYME INGNVEYAGV GWKEMRKRYA
GEVVYNQEDD DHLPTLTVAQ TIRFALATKT PKKKIPGVSA KQFQDDMLDL LLSMLNIKHT
ANTIVGNAFV RGVSGGERKR VSIAEMFCSG ATVCSWDNST RGLDASTALD YAKSLRLLTD
IMGQTTFVSL YQAGEGIYDQ FDKVLVLNEG HVAYFGPAKE ARQYMIGLGY RDLPRQTTAD
YLSGCTDVNE RRFADGRDAT NVPATPEEMG QAYRESEICA RMTREREEYK HLMAEDATAR
ENFKQAVLEQ KHKGVGKKSP YTVSFLQQVF IIFKRQLRLK FQDHFGISTG FATSIIIALI
VGSVYFRLPE TASGAFTRGG LLFLGLLFNA LTSFSELPSQ MLGRSVLYRQ NEYRFYRPAA
FALAAVLADV PYNASVIFLF SIVLYFMGGL YSSGGAFFMF FLFVFLTFMV MSAFFRTLGV
ATSDYNVAAR LASVLISFMV TYTGYMIPVQ RMKRWLFWIF YLNPLSYGYE AIFANEFSRI
SLTCDSSYTI PRNIPEAGIT GYPDTLGPNQ MCSIFGSTPG DPNVSGSDYM AVGYSYYKAH
IWRNFGILLG FFTFFMFLQM LFIEVLEQGA KHFSINVYKK EDKDLKAKNE RLAERREAFR
AGELEQDLSE LKMRPEPFTW EGLSYTVPVP GGHRQLLNDI YGYVKPGSLT ALMGASGAGK
TTLLDVLASR KNIGVVEGDI LMNGRPIGTD FQRGCAYAEQ QDTHEWTTTV REALQYSAYL
RQPQHVPKQE KDDYVEDIIE LLELQELADA MIGFPNYGLS VEARKRVTIG VELAAKPELL
LFLDEPTSGL DGQSAYNIVR FLKKLCAAGQ KILCTIHQPN ALLFQSFDRL LLLQRGGECV
YFGDIGPDSK VLIDYLERNG AEVPHDANPA EFMLEAIGAG SRKRIGSDWG EKWRNSPEFA
EVKREIQELK AEALAKPIEE KSNRTEYATS FLFQLKTVLH RTNVALWRNA DYQWTRLFAH
LAIGLIVTLT FLQLDNSVQS LQYRVFAIFF ATVLPALILA QIEPQYIMSR MTFNREASSK
MYSSTVFALT QLLSEMPYSL GCAVSFFLLL YYGVGFPYAS SRAGYFFLMI LVTEVYAVTL
GQAVAALSPT ILIAALFNPF LLVLFSIFCG VTAPPPTLPY FWRKWMWPLD PFTRLISGLV
STVLQDQEVV CKDGEYQVFP APSGQTCQQW AGAFAEAVGG YINNPDSTGD CQFCQYRSGQ
AFFVPLEISF STRWRDFGIF ICYVVFNILV LLIAARFLKW QRR
