P27352 (IF_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Gastric intrinsic factor

Alternative name(s):
Intrinsic factor
Short name=IF
Short name=INF

Gene names

Name:	GIF
Synonyms:	IFMH

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	417 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Promotes absorption of the essential vitamin cobalamin (Cbl) in the ileum. After interaction with CUBN, the GIF-cobalamin complex is internalized via receptor-mediated endocytosis.
Subunit structure	Interacts with CUBN (via CUB domains). Ref.7
Subcellular location	Secreted.
Tissue specificity	Gastric mucosa.
Involvement in disease	Hereditary intrinsic factor deficiency (IFD) [MIM:261000]: Autosomal recessive disorder characterized by megaloblastic anemia. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.9
Sequence similarities	Belongs to the eukaryotic cobalamin transport proteins family.

Ontologies

Keywords
Biological process	Cobalt transport Ion transport Transport
Cellular component	Secreted
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Disease mutation
Domain	Signal
Ligand	Cobalt
PTM	Disulfide bond Glycoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	cobalamin metabolic process Inferred from Biological aspect of Ancestor. Source: RefGenome cobalamin transport Inferred from mutant phenotype Ref.9. Source: UniProtKB cobalt ion transport Inferred from electronic annotation. Source: UniProtKB-KW
Cellular_component	apical plasma membrane Inferred from direct assay PubMed 8886952. Source: UniProtKB endosome Inferred from direct assay PubMed 8886952. Source: UniProtKB extracellular space Inferred from direct assay Ref.8. Source: UniProtKB microvillus Inferred from direct assay PubMed 8886952. Source: UniProtKB
Molecular_function	cobalamin binding Inferred from direct assay Ref.8. Source: UniProtKB
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P27352-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: P27352-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-27: MAWFALYLLSLLWATAGTSTQTQSSCS → MA

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 18

18

Potential

Chain

19 – 417

399

Gastric intrinsic factor

PRO_0000005558

Regions

Region

365 – 370

6

Cobalamin binding

Region

386 – 395

10

Cobalamin binding

Sites

Binding site

171

1

Cobalamin

Binding site

222

1

Cobalamin

Binding site

270

1

Cobalamin

Amino acid modifications

Glycosylation

311

1

N-linked (GlcNAc...) Ref.7

Glycosylation

330

1

N-linked (GlcNAc...) Potential

Glycosylation

334

1

N-linked (GlcNAc...) Potential

Glycosylation

413

1

N-linked (GlcNAc...) Ref.6 Ref.7

Disulfide bond

26 ↔ 246

Ref.6 Ref.7

Disulfide bond

103 ↔ 288

Ref.6 Ref.7

Disulfide bond

143 ↔ 182

Ref.6 Ref.7

Natural variations

Alternative sequence

1 – 27

27

MAWFA…QSSCS → MA in isoform 2.

VSP_041585

Natural variant

23

1

Q → R. Ref.8 Ref.9
Corresponds to variant rs35211634 [ dbSNP | Ensembl ].

VAR_022742

Natural variant

46

1

S → L in IFD. Ref.9

VAR_022743

Natural variant

65

1

G → R.
Corresponds to variant rs11825834 [ dbSNP | Ensembl ].

VAR_048753

Natural variant

255

1

N → S. Ref.9
Corresponds to variant rs35867471 [ dbSNP | Ensembl ].

VAR_022744

Experimental info

Sequence conflict

11

1

L → P in BAG36935. Ref.3

Sequence conflict

91

1

Q → H in AAA66354. Ref.1

Sequence conflict

96

1

I → V in BAG62853. Ref.3

Sequence conflict

264

1

N → D in BAG36935. Ref.3

Secondary structure

1

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417

Helix Strand Turn

Details...

Turn

30 – 32

3

Helix

33 – 44

12

Beta strand

49 – 51

3

Helix

55 – 64

10

Helix

69 – 80

12

Helix

84 – 86

3

Helix

89 – 101

13

Helix

108 – 118

11

Helix

129 – 132

4

Helix

133 – 145

13

Helix

147 – 163

17

Helix

170 – 184

15

Helix

195 – 210

16

Beta strand

220 – 222

3

Helix

223 – 235

13

Helix

246 – 257

12

Turn

258 – 262

5

Helix

265 – 275

11

Helix

280 – 285

6

Beta strand

311 – 319

9

Beta strand

333 – 339

7

Helix

343 – 352

10

Helix

355 – 357

3

Beta strand

359 – 364

6

Beta strand

367 – 375

9

Helix

380 – 382

3

Beta strand

384 – 390

7

Turn

399 – 401

3

Beta strand

409 – 416

8

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified April 26, 2005. Version 2. Checksum: F8B376E03A3D0F3C	FASTA	417	45,416
	10 20 30 40 50 60 MAWFALYLLS LLWATAGTST QTQSSCSVPS AQEPLVNGIQ VLMENSVTSS AYPNPSILIA 70 80 90 100 110 120 MNLAGAYNLK AQKLLTYQLM SSDNNDLTIG QLGLTIMALT SSCRDPGDKV SILQRQMENW 130 140 150 160 170 180 APSSPNAEAS AFYGPSLAIL ALCQKNSEAT LPIAVRFAKT LLANSSPFNV DTGAMATLAL 190 200 210 220 230 240 TCMYNKIPVG SEEGYRSLFG QVLKDIVEKI SMKIKDNGII GDIYSTGLAM QALSVTPEPS 250 260 270 280 290 300 KKEWNCKKTT DMILNEIKQG KFHNPMSIAQ ILPSLKGKTY LDVPQVTCSP DHEVQPTLPS 310 320 330 340 350 360 NPGPGPTSAS NITVIYTINN QLRGVELLFN ETINVSVKSG SVLLVVLEEA QRKNPMFKFE 370 380 390 400 410 TTMTSWGLVV SSINNIAENV NHKTYWQFLS GVTPLNEGVA DYIPFNHEHI TANFTQY
	Isoform 2 [UniParc]. Checksum: F86FC9448C15FDFC	FASTA	392	42,698
	10 20 30 40 50 60 MAVPSAQEPL VNGIQVLMEN SVTSSAYPNP SILIAMNLAG AYNLKAQKLL TYQLMSSDNN 70 80 90 100 110 120 DLTIGQLGLT IMALTSSCRD PGDKVSILQR QMENWAPSSP NAEASAFYGP SLAILALCQK 130 140 150 160 170 180 NSEATLPIAV RFAKTLLANS SPFNVDTGAM ATLALTCMYN KIPVGSEEGY RSLFGQVLKD 190 200 210 220 230 240 IVEKISMKIK DNGIIGDIYS TGLAMQALSV TPEPSKKEWN CKKTTDMILN EIKQGKFHNP 250 260 270 280 290 300 MSIAQILPSL KGKTYLDVPQ VTCSPDHEVQ PTLPSNPGPG PTSASNITVI YTINNQLRGV 310 320 330 340 350 360 ELLFNETINV SVKSGSVLLV VLEEAQRKNP MFKFETTMTS WGLVVSSINN IAENVNHKTY 370 380 390 WQFLSGVTPL NEGVADYIPF NHEHITANFT QY

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Human gastric intrinsic factor: characterization of cDNA and genomic clones and localization to human chromosome 11." Hewitt J.E., Gordon M.M., Taggart R.T., Mohandas T.K., Alpers D.H. Genomics 10:432-440(1991) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[2]	"A cDNA sequence of the human intrinsic factor." Hannappel M., Kehl M., Winnacker E.L. Submitted (APR-1994) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). Tissue: Stomach.
[3]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). Tissue: Stomach.
[4]	"Human chromosome 11 DNA sequence and analysis including novel gene identification." Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K., Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T., Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G. , Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C., Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A., Hattori M., Rogers J., Lander E.S., Sakaki Y. Nature 440:497-500(2006) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). Tissue: Colon.
[6]	"Crystal structure of human intrinsic factor: cobalamin complex at 2.6-A resolution." Mathews F.S., Gordon M.M., Chen Z., Rajashankar K.R., Ealick S.E., Alpers D.H., Sukumar N. Proc. Natl. Acad. Sci. U.S.A. 104:17311-17316(2007) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 19-417 IN COMPLEX WITH COBALAMIN, DISULFIDE BONDS, GLYCOSYLATION AT ASN-413.
[7]	"Structural basis for receptor recognition of vitamin-B(12)-intrinsic factor complexes." Andersen C.B., Madsen M., Storm T., Moestrup S.K., Andersen G.R. Nature 464:445-448(2010) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (3.3 ANGSTROMS) OF 25-417 IN COMPLEX WITH COBALAMIN AND CUBN, INTERACTION WITH CUBN, DISULFIDE BONDS, GLYCOSYLATION AT ASN-311 AND ASN-413.
[8]	"A genetic polymorphism in the coding region of the gastric intrinsic factor gene (GIF) is associated with congenital intrinsic factor deficiency." Gordon M.M., Brada N., Remacha A., Badell I., del Rio E., Baiget M., Santer R., Quadros E.V., Rothenberg S.P., Alpers D.H. Hum. Mutat. 23:85-91(2004) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT ARG-23.
[9]	"Hereditary juvenile cobalamin deficiency caused by mutations in the intrinsic factor gene." Tanner S.M., Li Z., Perko J.D., Oener C., Cetin M., Altay C., Yurtsever Z., David K.L., Faivre L., Ismail E.A., Graesbeck R., de la Chapelle A. Proc. Natl. Acad. Sci. U.S.A. 102:4130-4133(2005) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT IFD LEU-46, VARIANTS ARG-23 AND SER-255.
+	Additional computationally mapped references.

Web resources

GeneReviews

Wikipedia

Intrinsic factor entry

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

M63154 mRNA. Translation: AAA66354.1.
X76562 mRNA. Translation: CAA54061.1.
AK314275 mRNA. Translation: BAG36935.1.
AK301295 mRNA. Translation: BAG62853.1.
AP002347 Genomic DNA. No translation available.
BC037958 mRNA. Translation: AAH37958.1.

IPI

IPI00018169.
IPI01011862.

PIR

A39904.

RefSeq

NP_005133.2. NM_005142.2.

UniGene

Hs.110014.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2CKT	model	-	X	19-417	[»]
2PMV	X-ray	2.60	A/B/C/D	19-417	[»]
3KQ4	X-ray	3.30	A/C/E	25-417	[»]

ProteinModelPortal

P27352.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-46206N.

IntAct

P27352. 1 interaction.

STRING

9606.ENSP00000257248.

PTM databases

PhosphoSite

P27352.

Polymorphism databases

DMDM

62906845.

Proteomic databases

PaxDb

P27352.

PRIDE

P27352.

Protocols and materials databases

DNASU

2694.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000257248; ENSP00000257248; ENSG00000134812.
ENST00000541311; ENSP00000440427; ENSG00000134812.

GeneID

2694.

KEGG

hsa:2694.

UCSC

uc001noi.3. human.

Organism-specific databases

CTD

2694.

GeneCards

GC11M059596.

HGNC

HGNC:4268. GIF.

HPA

HPA039908.
HPA040774.

MIM

261000. phenotype.
609342. gene.

neXtProt

NX_P27352.

Orphanet

332. Congenital intrinsic factor deficiency.

PharmGKB

PA28678.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG45775.

HOGENOM

HOG000013214.

HOVERGEN

HBG006133.

InParanoid

P27352.

KO

K14615.

OMA

NLAGAYN.

OrthoDB

EOG4VX258.

PhylomeDB

P27352.

Gene expression databases

ArrayExpress

P27352.

Bgee

P27352.

CleanEx

HS_GIF.

Genevestigator

P27352.

GermOnline

ENSG00000134812. Homo sapiens.

Family and domain databases

InterPro

IPR002157. Cbl-bd_transpt_euk.
[Graphical view]

PANTHER

PTHR10559. PTHR10559. 1 hit.

Pfam

PF01122. Cobalamin_bind. 1 hit.
[Graphical view]

PROSITE

PS00468. COBALAMIN_BINDING. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

ChiTaRS

GIF. human.

EvolutionaryTrace

P27352.

GenomeRNAi

2694.

NextBio

10656.

SOURCE

Search...

Entry information

Entry name

IF_HUMAN

Accession

Primary (citable) accession number: P27352
Secondary accession number(s): B2RAN8, B4DVZ1

Entry history

Integrated into UniProtKB/Swiss-Prot:	August 1, 1992
Last sequence update:	April 26, 2005
Last modified:	May 1, 2013
This is version 120 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.