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 27-MAR-2024, entry version 193. 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"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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 GlyCosmos; P27352; 4 sites, No reported glycans. 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; 9606-ENSP00000257248; -. DR PeptideAtlas; P27352; -. DR ProteomicsDB; 54381; -. [P27352-1] DR ProteomicsDB; 54382; -. [P27352-2] DR Antibodypedia; 27824; 344 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 AGR; HGNC:4268; -. 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; 5361436at2759; -. 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 1131 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 115 other cell types or tissues. DR ExpressionAtlas; P27352; baseline and differential. DR GO; GO:0016324; C:apical plasma membrane; IDA:UniProtKB. DR GO; GO:0005768; C:endosome; IDA:UniProtKB. 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; EXP:Reactome. DR GO; GO:0031419; F:cobalamin binding; IDA:UniProtKB. DR GO; GO:0015889; P:cobalamin transport; IMP:UniProtKB. DR GO; GO:0006824; P:cobalt ion transport; IEA:UniProtKB-KW. DR Gene3D; 1.50.10.20; -; 1. DR Gene3D; 2.170.130.30; -; 1. DR InterPro; IPR002157; Cbl-bd_prot. DR PANTHER; PTHR10559:SF15; COBALAMIN BINDING INTRINSIC FACTOR; 1. DR PANTHER; PTHR10559; TRANSCOBALAMIN-1/GASTRIC INTRINSIC FACTOR; 1. DR Pfam; PF01122; Cobalamin_bind; 1. DR PROSITE; PS00468; COBALAMIN_BINDING; 1. DR Genevisible; P27352; HS. 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 //