AFR2_CRYNH
ID AFR2_CRYNH Reviewed; 1529 AA.
AC J9VPA2;
DT 02-JUN-2021, integrated into UniProtKB/Swiss-Prot.
DT 28-NOV-2012, sequence version 1.
DT 03-AUG-2022, entry version 49.
DE RecName: Full=ABC multidrug transporter AFR2 {ECO:0000303|PubMed:25630649};
GN Name=AFR2 {ECO:0000303|PubMed:25630649}; ORFNames=CNAG_00869;
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: Pleiotropic ABC efflux transporter that confers resistance to
CC structurally and functionally unrelated compounds including azoles such
CC as fluconazole (FLC), itraconazole (ITC), posaconazole (POS), and
CC voriconazole (VRC). {ECO:0000269|PubMed:25630649,
CC 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=0.13 uM for fluconazole transport {ECO:0000269|PubMed:25630649};
CC Vmax=2.60 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: Does not affect the susceptibility to azoles
CC (PubMed:29378705). Causes further increase in susceptibility toward
CC fluconazole and itraconazole, when AFR1 and MDR1 are also deleted
CC (PubMed:29378705). {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; CP003824; AFR95261.1; -; Genomic_DNA.
DR RefSeq; XP_012049160.1; XM_012193770.1.
DR AlphaFoldDB; J9VPA2; -.
DR SMR; J9VPA2; -.
DR EnsemblFungi; AFR95261; AFR95261; CNAG_00869.
DR GeneID; 23884643; -.
DR VEuPathDB; FungiDB:CNAG_00869; -.
DR HOGENOM; CLU_000604_35_0_1; -.
DR Proteomes; UP000010091; Chromosome 5.
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:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0042626; F:ATPase-coupled transmembrane transporter activity; IEA:InterPro.
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; 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; PF00005; ABC_tran; 2.
DR Pfam; PF14510; ABC_trans_N; 1.
DR Pfam; PF06422; PDR_CDR; 1.
DR SMART; SM00382; AAA; 2.
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..1529
FT /note="ABC multidrug transporter AFR2"
FT /id="PRO_0000452664"
FT TRANSMEM 505..525
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 539..559
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 589..609
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 614..634
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 648..668
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 757..777
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 1193..1213
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 1227..1247
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 1268..1288
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 1314..1334
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 1353..1373
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 1465..1485
FT /note="Helical"
FT /evidence="ECO:0000255"
FT DOMAIN 144..394
FT /note="ABC transporter 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00434"
FT DOMAIN 845..1087
FT /note="ABC transporter 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00434"
FT REGION 1..21
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1493..1529
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 881..888
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00434"
FT CARBOHYD 235
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 318
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 742
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 1434
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ SEQUENCE 1529 AA; 169783 MW; 73DAF03A1313AC11 CRC64;
MAFAGVGQGL GTYDRTEQTS GASLGRVASR AHFTDTHPSD DLPAQTEEHR AREVGHLARQ
LTRQSVGGTD DSSALFSYQQ GSDLDPFSDK FCARRWTKLM FEALQTSGPA RKAGLSFRNL
DVHGFGSDAD YQKTVGNLPL VGIGALRDLI SNRKRKVQIL NSMDGVLEAG EMLVVLGPPG
SGCTTMLKTI AGEMNGIYLD ESSSLNYRGI TPKQIYGQFR GEAIYTAEVD VHFPNLTVGQ
TLSFAAEARA PRNPPGGISK KEYAKHMRDV VMSVFGISHT LNTIVGNDFI RGVSGGERKR
VTIAEASLAG APLQCWDNST RGLDSANAIE FCKNLRLNAD YIGISSAVAI YQAPQAAYDC
FDKVSVLYEG EQIFFGKTTD AKQFFVDMGF HCPSQQTVPD FLTSLTSASE RTPREGFEGK
VPTTPQEFAA RWKQSDKYQE LLAQIAEFEN KYPVHGKNYQ EFLQSRRAQQ SKRLRAKSPY
TLSYGGQVEL CLRRGFDRLR ADPSLTLTQL FGNFIMALII GSVFYNLPAT TSSFYSRGAL
LFFAILMSAF GSALEILILY AQRGIVEKHS RYAFYHPSAE AVASALTDIP YKVINCIIFS
LTLYFMTNLR REPGPYFFFM LISFTLTMVM SMLFRSIASL SRSLAQALAP AALLILGLVM
YTGFAVNVAN MRGWARWMNW LDPIAYGFES LMINEFHDRE YECSAFIPMG PGYEGATGQQ
HVCSTAGAIA GSSVVNGDDY INLSYEYYHA HKWRNFGILI GFFLFFTAIY MTATEFITAK
KSKGEILVFP RGKIPRALLA QSTHSHGSSD DVEGGKFAGG SKMKKQITGA DRADAGIIQR
QTAIFSWKDV VYDIKIKKEP RRILDHVDGW VKPGTLTALM GVSGAGKTTL LDVLATRVTM
GVVTGEMLVD GRQRDVSFQR KTGYVQQQDL HLETSTVREA LRFSAVLRQS NTISIKEKYE
YVEEVLKLLE MESYADAVVG VPGTGLNVEQ RKRLTIGVEL VAKPALLLFL DEPTSGLDSQ
TSWNILLLLR KLTEHGQAIL CTIHQPSAML FEQFDRLLFL ARGGKTVYFG EVGKGSHILI
DYFEKNGAPK CPEGENPAEW MLAAIGAAPG SHSDVDWHQA WINSPERVEV RRELARIKET
QGGKGEAALQ NKDHEKSKSE VKAEYAEFAS PLWKQFNVVL TRVWQQHWRT PSYIWSKAAL
CALSALFIGF SFFKSGTSQQ GLQNQLFSVF MMFTIFGQLT QQIMPNFTTQ RSLYEVRERP
SKTYSWKIFI LSNIVAEIPW AILMGAVIYF TWYYPIGYYR NAIPTGAVHL RGALMFLYIE
MFLIFNATFA IMIVAGIATA ETAGNIANLL FSMCLIFCGV LAPPSSLPGF WMFMYRVSPF
TYLVDGMLST AVAETSVVCS DIELLTLNPP SGESCGDYMS TYISNYGGYL VNENATTACE
FCSMSSTNSF LAQFNIYYSN KWRDFGLLWA YVVFNIIAAV GIYWLARVPK NTGKEQASEP
EGVQEKLVPA QSSEKKRESV SRGSESTAA
