ID FLVC2_RAT Reviewed; 546 AA.
AC P60815;
DT 13-APR-2004, integrated into UniProtKB/Swiss-Prot.
DT 13-APR-2004, sequence version 1.
DT 27-MAR-2024, entry version 101.
DE RecName: Full=Heme transporter FLVCR2 {ECO:0000250|UniProtKB:Q9UPI3};
DE AltName: Full=Calcium-chelate transporter {ECO:0000250|UniProtKB:Q9UPI3};
DE Short=CCT {ECO:0000250|UniProtKB:Q9UPI3};
DE AltName: Full=Feline leukemia virus subgroup C receptor-related protein 2;
GN Name=Flvcr2;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND DEVELOPMENTAL STAGE.
RC TISSUE=Kidney;
RX PubMed=14729055; DOI=10.1016/j.yexcr.2003.10.002;
RA Brasier G., Tikellis C., Xuereb L., Craigie J., Casley D., Kovacs C.S.,
RA Fudge N.J., Kalnins R., Cooper M.E., Wookey P.J.;
RT "Novel hexad repeats conserved in a putative transporter with restricted
RT expression in cell types associated with growth, calcium exchange and
RT homeostasis.";
RL Exp. Cell Res. 293:31-42(2004).
CC -!- FUNCTION: Putative heme b importer/sensor involved in heme homeostasis
CC in response to the metabolic state of the cell and to diet. May act as
CC a sensor of cytosolic and/or mitochondrial heme levels to regulate
CC mitochondrial respiration processes, ATP synthesis and thermogenesis.
CC At low heme levels, interacts with components of electron transfer
CC chain (ETC) complexes and ATP2A2, leading to ubiquitin-mediated
CC degradation of ATP2A2 and inhibition of thermogenesis. Upon heme
CC binding, dissociates from ETC complexes to allow switching from
CC mitochondrial ATP synthesis to thermogenesis. Alternatively, in
CC coordination with ATP2A2 may mediate calcium transport and signaling in
CC response to heme. {ECO:0000250|UniProtKB:Q9UPI3}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=heme b(in) = heme b(out); Xref=Rhea:RHEA:75443,
CC ChEBI:CHEBI:60344; Evidence={ECO:0000250|UniProtKB:Q9UPI3};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:75444;
CC Evidence={ECO:0000250|UniProtKB:Q9UPI3};
CC -!- SUBUNIT: Interacts with components of electron transfer chain complexes
CC III, IV and V including CYC1, NDUFA4, COX4I1, ATP5PD and ATP5F1C; these
CC interactions occur in the absence of heme and are disrupted upon heme
CC binding. Interacts with ATP2A2; this interaction occurs in the absence
CC of heme and promotes ATP2A2 proteasomal degradation; the complex is
CC dissociated upon heme binding. Interacts with HMOX1; this interaction
CC is potentiated in the presence of heme. {ECO:0000250|UniProtKB:Q91X85}.
CC -!- SUBCELLULAR LOCATION: Mitochondrion membrane
CC {ECO:0000250|UniProtKB:Q9UPI3}; Multi-pass membrane protein
CC {ECO:0000255}. Endoplasmic reticulum membrane
CC {ECO:0000250|UniProtKB:Q91X85}; Multi-pass membrane protein
CC {ECO:0000255}. Cell membrane {ECO:0000250|UniProtKB:Q9UPI3}; Multi-pass
CC membrane protein {ECO:0000255}. Note=Primarily resides in mitochondria
CC where it interacts with components of the electron transfer chain
CC complexes III, IV and V. Colocalizes with ATP2A2 at the mitochondrial-
CC ER contact junction. {ECO:0000250|UniProtKB:Q91X85}.
CC -!- DEVELOPMENTAL STAGE: Expressed in the retinal pigment epithelial layer
CC at 18 dpc and in blood vessels of the developing retina (at protein
CC level). Expressed in cells lining the fourth ventricle and central
CC canal of the spinal cord at 17 dpc (at protein level).
CC {ECO:0000269|PubMed:14729055}.
CC -!- DOMAIN: The N-terminus contains histidine-proline motifs involved in
CC heme binding. Can bind 2 to 3 heme molecules.
CC {ECO:0000250|UniProtKB:Q9UPI3}.
CC -!- SIMILARITY: Belongs to the major facilitator superfamily. Feline
CC leukemia virus subgroup C receptor (TC 2.A.1.28.1) family.
CC {ECO:0000305}.
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DR EMBL; AY260573; AAP86634.1; -; mRNA.
DR AlphaFoldDB; P60815; -.
DR SMR; P60815; -.
DR STRING; 10116.ENSRNOP00000073434; -.
DR PhosphoSitePlus; P60815; -.
DR PaxDb; 10116-ENSRNOP00000011599; -.
DR UCSC; RGD:735098; rat.
DR AGR; RGD:735098; -.
DR RGD; 735098; Flvcr2.
DR eggNOG; KOG2563; Eukaryota.
DR InParanoid; P60815; -.
DR PhylomeDB; P60815; -.
DR ChiTaRS; Flvcr2; rat.
DR PRO; PR:P60815; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; ISS:UniProtKB.
DR GO; GO:0016020; C:membrane; IBA:GO_Central.
DR GO; GO:0031966; C:mitochondrial membrane; ISS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0020037; F:heme binding; ISS:UniProtKB.
DR GO; GO:0015232; F:heme transmembrane transporter activity; ISS:UniProtKB.
DR GO; GO:0097037; P:heme export; IBA:GO_Central.
DR Gene3D; 1.20.1250.20; MFS general substrate transporter like domains; 2.
DR InterPro; IPR011701; MFS.
DR InterPro; IPR020846; MFS_dom.
DR InterPro; IPR036259; MFS_trans_sf.
DR InterPro; IPR049680; SLC49-like.
DR PANTHER; PTHR10924:SF3; FELINE LEUKEMIA VIRUS SUBGROUP C RECEPTOR-RELATED PROTEIN 2; 1.
DR PANTHER; PTHR10924; MAJOR FACILITATOR SUPERFAMILY PROTEIN-RELATED; 1.
DR Pfam; PF07690; MFS_1; 1.
DR SUPFAM; SSF103473; MFS general substrate transporter; 1.
DR PROSITE; PS50850; MFS; 1.
PE 1: Evidence at protein level;
KW Cell membrane; Endoplasmic reticulum; Membrane; Mitochondrion;
KW Phosphoprotein; Reference proteome; Repeat; Transmembrane;
KW Transmembrane helix; Transport.
FT CHAIN 1..546
FT /note="Heme transporter FLVCR2"
FT /id="PRO_0000084848"
FT TRANSMEM 102..122
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 142..162
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 169..189
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 193..213
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 234..254
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 269..289
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 327..347
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 366..386
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 395..415
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 418..438
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 453..473
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 484..504
FT /note="Helical"
FT /evidence="ECO:0000255"
FT REPEAT 31..36
FT /note="1"
FT REPEAT 37..42
FT /note="2"
FT REPEAT 43..48
FT /note="3"
FT REPEAT 49..54
FT /note="4"
FT REPEAT 55..60
FT /note="5"
FT REPEAT 61..66
FT /note="6"
FT REPEAT 67..72
FT /note="7"
FT REPEAT 73..78
FT /note="8; approximate"
FT REPEAT 79..84
FT /note="9; approximate"
FT REGION 1..84
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 31..84
FT /note="9 X 6 AA tandem repeats of P-S-[VS]-S-[VIAG]-[HD]"
FT REGION 511..546
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 18..82
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 1..101
FT /ligand="heme b"
FT /ligand_id="ChEBI:CHEBI:60344"
FT /evidence="ECO:0000250|UniProtKB:Q9UPI3"
FT MOD_RES 535
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q91X85"
SQ SEQUENCE 546 AA; 59742 MW; 0E7B77D258295C45 CRC64;
MVNESLNQEE SNDRPVPESE FQADTSYSTQ PSVSIHPSVS GHPSVSIHPS VSGHPSVSID
PSVSVHPSSS AHPSTLAQPS GLTHPNELVK EDSVIKVSKR RWAVVLVFSC YSLCNAFQWI
QYGSINNIFM NFYGVSAFAI DWLSMCYMLT YIPLLLPVAW MLEKFGLRTI AITGSALNCL
GAWVKLGSLE PHLFPVTMVG QVICSVAQVF ILGMPSRIAS VWFGANEVST ACSMAVFGNQ
LGIAIGFLVP PVLVPNIKDQ EKLAYHISIM FYIIGGVATL LFILVIIVFK EKPKYPPSRA
QSLSYALATT DASYLSSIVR LFKNLNFVLL VITYGLNAGA FYALSTLLNR MVIMHFPGQE
VNAGRIGLTI VIAGMFGAMI SGIWLDKSKT YKETTLVVYI MTLVGMVVYT FTLNLNHLWI
VFITADSLGF FMTGYLPLGF EFAVELTYPE SEGVSSGLLN VSAQVFGIIF TISQGQIIDN
YGSVPGNIFL CVFLALGSAL TAFIKSDLRR QRANKDAPET KVQEEEEEEE ESNTSKVPTV
LSEAHL
//
