IF_HUMAN
ID IF_HUMAN Reviewed; 417 AA.
AC P27352; B2RAN8; B4DVZ1;
DT 01-AUG-1992, integrated into UniProtKB/Swiss-Prot.
DT 26-APR-2005, sequence version 2.
DT 03-AUG-2022, entry version 184.
DE RecName: Full=Cobalamin binding intrinsic factor {ECO:0000305};
DE AltName: Full=Gastric intrinsic factor {ECO:0000303|PubMed:2071148};
DE AltName: Full=Intrinsic factor;
DE Short=IF;
DE Short=INF;
DE Flags: Precursor;
GN Name=CBLIF {ECO:0000312|HGNC:HGNC:4268};
GN Synonyms=GIF {ECO:0000312|HGNC:HGNC:4268}, IFMH;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=2071148; DOI=10.1016/0888-7543(91)90329-d;
RA Hewitt J.E., Gordon M.M., Taggart R.T., Mohandas T.K., Alpers D.H.;
RT "Human gastric intrinsic factor: characterization of cDNA and genomic
RT clones and localization to human chromosome 11.";
RL Genomics 10:432-440(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Stomach;
RA Hannappel M., Kehl M., Winnacker E.L.;
RT "A cDNA sequence of the human intrinsic factor.";
RL Submitted (APR-1994) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Stomach;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16554811; DOI=10.1038/nature04632;
RA Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K.,
RA Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T.,
RA Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G.,
RA Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C.,
RA Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A.,
RA Hattori M., Rogers J., Lander E.S., Sakaki Y.;
RT "Human chromosome 11 DNA sequence and analysis including novel gene
RT identification.";
RL Nature 440:497-500(2006).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Colon;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6] {ECO:0007744|PDB:2PMV}
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 19-417 IN COMPLEX WITH COBALAMIN,
RP DISULFIDE BONDS, AND GLYCOSYLATION AT ASN-413.
RX PubMed=17954916; DOI=10.1073/pnas.0703228104;
RA Mathews F.S., Gordon M.M., Chen Z., Rajashankar K.R., Ealick S.E.,
RA Alpers D.H., Sukumar N.;
RT "Crystal structure of human intrinsic factor: cobalamin complex at 2.6-A
RT resolution.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:17311-17316(2007).
RN [7] {ECO:0007744|PDB:3KQ4}
RP X-RAY CRYSTALLOGRAPHY (3.3 ANGSTROMS) OF 25-417 IN COMPLEX WITH COBALAMIN
RP AND CUBN, INTERACTION WITH CUBN, DISULFIDE BONDS, AND GLYCOSYLATION AT
RP ASN-311 AND ASN-413.
RX PubMed=20237569; DOI=10.1038/nature08874;
RA Andersen C.B., Madsen M., Storm T., Moestrup S.K., Andersen G.R.;
RT "Structural basis for receptor recognition of vitamin-B(12)-intrinsic
RT factor complexes.";
RL Nature 464:445-448(2010).
RN [8]
RP VARIANT ARG-23.
RX PubMed=14695536; DOI=10.1002/humu.10297;
RA Gordon M.M., Brada N., Remacha A., Badell I., del Rio E., Baiget M.,
RA Santer R., Quadros E.V., Rothenberg S.P., Alpers D.H.;
RT "A genetic polymorphism in the coding region of the gastric intrinsic
RT factor gene (GIF) is associated with congenital intrinsic factor
RT deficiency.";
RL Hum. Mutat. 23:85-91(2004).
RN [9]
RP VARIANT IFD LEU-46, AND VARIANTS ARG-23 AND SER-255.
RX PubMed=15738392; DOI=10.1073/pnas.0500517102;
RA Tanner S.M., Li Z., Perko J.D., Oener C., Cetin M., Altay C., Yurtsever Z.,
RA David K.L., Faivre L., Ismail E.A., Graesbeck R., de la Chapelle A.;
RT "Hereditary juvenile cobalamin deficiency caused by mutations in the
RT intrinsic factor gene.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:4130-4133(2005).
CC -!- FUNCTION: Promotes absorption of the essential vitamin cobalamin (Cbl)
CC in the ileum. After interaction with CUBN, the CBLIF-cobalamin complex
CC is internalized via receptor-mediated endocytosis.
CC -!- SUBUNIT: Interacts with CUBN (via CUB domains).
CC {ECO:0000269|PubMed:17954916, ECO:0000269|PubMed:20237569}.
CC -!- INTERACTION:
CC P27352; O60494: CUBN; NbExp=2; IntAct=EBI-3953638, EBI-3953632;
CC P27352; O15552: FFAR2; NbExp=3; IntAct=EBI-3953638, EBI-2833872;
CC P27352; Q9UKG4: SLC13A4; NbExp=3; IntAct=EBI-3953638, EBI-12808018;
CC P27352; A1A5C7-2: SLC22A23; NbExp=3; IntAct=EBI-3953638, EBI-12081840;
CC P27352; P30825: SLC7A1; NbExp=3; IntAct=EBI-3953638, EBI-4289564;
CC P27352; Q8TBB6: SLC7A14; NbExp=3; IntAct=EBI-3953638, EBI-5235586;
CC P27352; Q96Q45-2: TMEM237; NbExp=3; IntAct=EBI-3953638, EBI-10982110;
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P27352-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P27352-2; Sequence=VSP_041585;
CC -!- TISSUE SPECIFICITY: Gastric mucosa.
CC -!- DISEASE: Hereditary intrinsic factor deficiency (IFD) [MIM:261000]:
CC Autosomal recessive disorder characterized by megaloblastic anemia.
CC {ECO:0000269|PubMed:15738392}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the eukaryotic cobalamin transport proteins
CC family. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Intrinsic factor entry;
CC URL="https://en.wikipedia.org/wiki/Intrinsic_factor";
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DR EMBL; M63154; AAA66354.1; -; mRNA.
DR EMBL; X76562; CAA54061.1; -; mRNA.
DR EMBL; AK314275; BAG36935.1; -; mRNA.
DR EMBL; AK301295; BAG62853.1; -; mRNA.
DR EMBL; AP002347; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC037958; AAH37958.1; -; mRNA.
DR CCDS; CCDS7977.1; -. [P27352-1]
DR PIR; A39904; A39904.
DR RefSeq; NP_005133.2; NM_005142.2. [P27352-1]
DR PDB; 2PMV; X-ray; 2.60 A; A/B/C/D=19-417.
DR PDB; 3KQ4; X-ray; 3.30 A; A/C/E=25-417.
DR PDBsum; 2PMV; -.
DR PDBsum; 3KQ4; -.
DR AlphaFoldDB; P27352; -.
DR SMR; P27352; -.
DR BioGRID; 108961; 15.
DR CORUM; P27352; -.
DR DIP; DIP-46206N; -.
DR IntAct; P27352; 11.
DR MINT; P27352; -.
DR STRING; 9606.ENSP00000257248; -.
DR DrugBank; DB00115; Cyanocobalamin.
DR GlyGen; P27352; 4 sites.
DR iPTMnet; P27352; -.
DR PhosphoSitePlus; P27352; -.
DR BioMuta; GIF; -.
DR DMDM; 62906845; -.
DR EPD; P27352; -.
DR MassIVE; P27352; -.
DR PaxDb; P27352; -.
DR PeptideAtlas; P27352; -.
DR PRIDE; P27352; -.
DR ProteomicsDB; 54381; -. [P27352-1]
DR ProteomicsDB; 54382; -. [P27352-2]
DR Antibodypedia; 27824; 317 antibodies from 26 providers.
DR DNASU; 2694; -.
DR Ensembl; ENST00000257248.3; ENSP00000257248.2; ENSG00000134812.8. [P27352-1]
DR GeneID; 2694; -.
DR KEGG; hsa:2694; -.
DR MANE-Select; ENST00000257248.3; ENSP00000257248.2; NM_005142.3; NP_005133.2.
DR UCSC; uc001noi.4; human. [P27352-1]
DR CTD; 2694; -.
DR DisGeNET; 2694; -.
DR GeneCards; CBLIF; -.
DR HGNC; HGNC:4268; CBLIF.
DR HPA; ENSG00000134812; Tissue enriched (stomach).
DR MalaCards; CBLIF; -.
DR MIM; 261000; phenotype.
DR MIM; 609342; gene.
DR neXtProt; NX_P27352; -.
DR OpenTargets; ENSG00000134812; -.
DR Orphanet; 332; Congenital intrinsic factor deficiency.
DR PharmGKB; PA28678; -.
DR VEuPathDB; HostDB:ENSG00000134812; -.
DR eggNOG; ENOG502RXIA; Eukaryota.
DR GeneTree; ENSGT00530000063370; -.
DR HOGENOM; CLU_052188_2_0_1; -.
DR InParanoid; P27352; -.
DR OMA; AYNVEAQ; -.
DR OrthoDB; 1233171at2759; -.
DR PhylomeDB; P27352; -.
DR TreeFam; TF333092; -.
DR PathwayCommons; P27352; -.
DR Reactome; R-HSA-3359457; Defective CBLIF causes IFD.
DR Reactome; R-HSA-3359462; Defective AMN causes MGA1.
DR Reactome; R-HSA-3359463; Defective CUBN causes MGA1.
DR Reactome; R-HSA-9758881; Uptake of dietary cobalamins into enterocytes.
DR SignaLink; P27352; -.
DR BioGRID-ORCS; 2694; 12 hits in 1057 CRISPR screens.
DR ChiTaRS; GIF; human.
DR EvolutionaryTrace; P27352; -.
DR GeneWiki; Intrinsic_factor; -.
DR GenomeRNAi; 2694; -.
DR Pharos; P27352; Tbio.
DR PRO; PR:P27352; -.
DR Proteomes; UP000005640; Chromosome 11.
DR RNAct; P27352; protein.
DR Bgee; ENSG00000134812; Expressed in cardia of stomach and 113 other tissues.
DR ExpressionAtlas; P27352; baseline and differential.
DR Genevisible; P27352; HS.
DR GO; GO:0016324; C:apical plasma membrane; IDA:UniProtKB.
DR GO; GO:0005768; C:endosome; IDA:UniProtKB.
DR GO; GO:0098591; C:external side of apical plasma membrane; IEA:Ensembl.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB.
DR GO; GO:0043202; C:lysosomal lumen; TAS:Reactome.
DR GO; GO:0005902; C:microvillus; IDA:UniProtKB.
DR GO; GO:0140355; F:cargo receptor ligand activity; IEA:Ensembl.
DR GO; GO:0031419; F:cobalamin binding; IDA:UniProtKB.
DR GO; GO:0009235; P:cobalamin metabolic process; IEA:Ensembl.
DR GO; GO:0015889; P:cobalamin transport; IMP:UniProtKB.
DR GO; GO:0006824; P:cobalt ion transport; IEA:UniProtKB-KW.
DR InterPro; IPR002157; Cbl-bd_prot.
DR InterPro; IPR027954; DUF4430.
DR Pfam; PF01122; Cobalamin_bind; 1.
DR Pfam; PF14478; DUF4430; 1.
DR PROSITE; PS00468; COBALAMIN_BINDING; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cobalt; Cobalt transport;
KW Disease variant; Disulfide bond; Glycoprotein; Ion transport;
KW Phosphoprotein; Reference proteome; Secreted; Signal; Transport.
FT SIGNAL 1..18
FT /evidence="ECO:0000255"
FT CHAIN 19..417
FT /note="Cobalamin binding intrinsic factor"
FT /id="PRO_0000005558"
FT BINDING 171
FT /ligand="cob(II)alamin"
FT /ligand_id="ChEBI:CHEBI:16304"
FT /evidence="ECO:0000269|PubMed:17954916,
FT ECO:0000269|PubMed:20237569"
FT BINDING 222
FT /ligand="cob(II)alamin"
FT /ligand_id="ChEBI:CHEBI:16304"
FT /evidence="ECO:0000269|PubMed:17954916,
FT ECO:0000269|PubMed:20237569"
FT BINDING 270
FT /ligand="cob(II)alamin"
FT /ligand_id="ChEBI:CHEBI:16304"
FT /evidence="ECO:0000269|PubMed:17954916,
FT ECO:0000269|PubMed:20237569"
FT BINDING 365..370
FT /ligand="cob(II)alamin"
FT /ligand_id="ChEBI:CHEBI:16304"
FT BINDING 386..395
FT /ligand="cob(II)alamin"
FT /ligand_id="ChEBI:CHEBI:16304"
FT MOD_RES 191
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P17267"
FT CARBOHYD 311
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:20237569"
FT CARBOHYD 330
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 334
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 413
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:17954916,
FT ECO:0000269|PubMed:20237569"
FT DISULFID 26..246
FT DISULFID 103..288
FT DISULFID 143..182
FT VAR_SEQ 1..27
FT /note="MAWFALYLLSLLWATAGTSTQTQSSCS -> MA (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_041585"
FT VARIANT 23
FT /note="Q -> R (in dbSNP:rs35211634)"
FT /evidence="ECO:0000269|PubMed:14695536,
FT ECO:0000269|PubMed:15738392"
FT /id="VAR_022742"
FT VARIANT 46
FT /note="S -> L (in IFD; dbSNP:rs121434322)"
FT /evidence="ECO:0000269|PubMed:15738392"
FT /id="VAR_022743"
FT VARIANT 65
FT /note="G -> R (in dbSNP:rs11825834)"
FT /id="VAR_048753"
FT VARIANT 255
FT /note="N -> S (in dbSNP:rs35867471)"
FT /evidence="ECO:0000269|PubMed:15738392"
FT /id="VAR_022744"
FT CONFLICT 11
FT /note="L -> P (in Ref. 3; BAG36935)"
FT /evidence="ECO:0000305"
FT CONFLICT 91
FT /note="Q -> H (in Ref. 1; AAA66354)"
FT /evidence="ECO:0000305"
FT CONFLICT 96
FT /note="I -> V (in Ref. 3; BAG62853)"
FT /evidence="ECO:0000305"
FT CONFLICT 264
FT /note="N -> D (in Ref. 3; BAG36935)"
FT /evidence="ECO:0000305"
FT TURN 30..32
FT /evidence="ECO:0007829|PDB:3KQ4"
FT HELIX 33..44
FT /evidence="ECO:0007829|PDB:2PMV"
FT STRAND 49..51
FT /evidence="ECO:0007829|PDB:2PMV"
FT HELIX 55..64
FT /evidence="ECO:0007829|PDB:2PMV"
FT HELIX 69..80
FT /evidence="ECO:0007829|PDB:2PMV"
FT HELIX 84..86
FT /evidence="ECO:0007829|PDB:2PMV"
FT HELIX 89..101
FT /evidence="ECO:0007829|PDB:2PMV"
FT HELIX 108..118
FT /evidence="ECO:0007829|PDB:2PMV"
FT HELIX 129..132
FT /evidence="ECO:0007829|PDB:2PMV"
FT HELIX 133..145
FT /evidence="ECO:0007829|PDB:2PMV"
FT HELIX 147..163
FT /evidence="ECO:0007829|PDB:2PMV"
FT HELIX 170..184
FT /evidence="ECO:0007829|PDB:2PMV"
FT HELIX 195..210
FT /evidence="ECO:0007829|PDB:2PMV"
FT STRAND 220..222
FT /evidence="ECO:0007829|PDB:2PMV"
FT HELIX 223..235
FT /evidence="ECO:0007829|PDB:2PMV"
FT HELIX 246..257
FT /evidence="ECO:0007829|PDB:2PMV"
FT TURN 258..262
FT /evidence="ECO:0007829|PDB:2PMV"
FT HELIX 265..275
FT /evidence="ECO:0007829|PDB:2PMV"
FT HELIX 280..285
FT /evidence="ECO:0007829|PDB:2PMV"
FT STRAND 311..319
FT /evidence="ECO:0007829|PDB:2PMV"
FT STRAND 333..339
FT /evidence="ECO:0007829|PDB:2PMV"
FT HELIX 343..352
FT /evidence="ECO:0007829|PDB:2PMV"
FT HELIX 355..357
FT /evidence="ECO:0007829|PDB:3KQ4"
FT STRAND 359..364
FT /evidence="ECO:0007829|PDB:2PMV"
FT STRAND 367..375
FT /evidence="ECO:0007829|PDB:2PMV"
FT HELIX 380..382
FT /evidence="ECO:0007829|PDB:2PMV"
FT STRAND 384..390
FT /evidence="ECO:0007829|PDB:2PMV"
FT TURN 399..401
FT /evidence="ECO:0007829|PDB:2PMV"
FT STRAND 409..416
FT /evidence="ECO:0007829|PDB:2PMV"
SQ SEQUENCE 417 AA; 45416 MW; F8B376E03A3D0F3C CRC64;
MAWFALYLLS LLWATAGTST QTQSSCSVPS AQEPLVNGIQ VLMENSVTSS AYPNPSILIA
MNLAGAYNLK AQKLLTYQLM SSDNNDLTIG QLGLTIMALT SSCRDPGDKV SILQRQMENW
APSSPNAEAS AFYGPSLAIL ALCQKNSEAT LPIAVRFAKT LLANSSPFNV DTGAMATLAL
TCMYNKIPVG SEEGYRSLFG QVLKDIVEKI SMKIKDNGII GDIYSTGLAM QALSVTPEPS
KKEWNCKKTT DMILNEIKQG KFHNPMSIAQ ILPSLKGKTY LDVPQVTCSP DHEVQPTLPS
NPGPGPTSAS NITVIYTINN QLRGVELLFN ETINVSVKSG SVLLVVLEEA QRKNPMFKFE
TTMTSWGLVV SSINNIAENV NHKTYWQFLS GVTPLNEGVA DYIPFNHEHI TANFTQY
