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Protein

Macrophage migration inhibitory factor

Gene

Mif

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Pro-inflammatory cytokine. Involved in the innate immune response to bacterial pathogens. The expression of MIF at sites of inflammation suggests a role as mediator in regulating the function of macrophages in host defense. Counteracts the anti-inflammatory activity of glucocorticoids. Has phenylpyruvate tautomerase and dopachrome tautomerase activity (in vitro), but the physiological substrate is not known. It is not clear whether the tautomerase activity has any physiological relevance, and whether it is important for cytokine activity (By similarity).By similarity

Catalytic activityi

Keto-phenylpyruvate = enol-phenylpyruvate.1 Publication
L-dopachrome = 5,6-dihydroxyindole-2-carboxylate.1 Publication

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Active sitei2 – 21Proton acceptor; via imino nitrogen
Binding sitei33 – 331Substrate
Binding sitei65 – 651Substrate; via amide nitrogenBy similarity
Binding sitei98 – 981Substrate

GO - Molecular functioni

  • chemoattractant activity Source: MGI
  • cytokine activity Source: BHF-UCL
  • cytokine receptor binding Source: MGI
  • dopachrome isomerase activity Source: UniProtKB
  • phenylpyruvate tautomerase activity Source: MGI
  • receptor binding Source: MGI

GO - Biological processi

  • carboxylic acid metabolic process Source: MGI
  • cell aging Source: MGI
  • cell proliferation Source: MGI
  • cell surface receptor signaling pathway Source: MGI
  • DNA damage response, signal transduction by p53 class mediator Source: MGI
  • inflammatory response Source: UniProtKB-KW
  • innate immune response Source: UniProtKB-KW
  • negative regulation of apoptotic process Source: BHF-UCL
  • negative regulation of cell aging Source: MGI
  • negative regulation of cell cycle arrest Source: MGI
  • negative regulation of cellular protein metabolic process Source: BHF-UCL
  • negative regulation of DNA damage response, signal transduction by p53 class mediator Source: BHF-UCL
  • negative regulation of gene expression Source: MGI
  • negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator Source: MGI
  • negative regulation of mature B cell apoptotic process Source: BHF-UCL
  • negative regulation of myeloid cell apoptotic process Source: BHF-UCL
  • positive chemotaxis Source: MGI
  • positive regulation of adaptive immune response Source: BHF-UCL
  • positive regulation of arachidonic acid secretion Source: BHF-UCL
  • positive regulation of B cell proliferation Source: MGI
  • positive regulation of chemokine (C-X-C motif) ligand 2 production Source: BHF-UCL
  • positive regulation of cytokine secretion Source: MGI
  • positive regulation of ERK1 and ERK2 cascade Source: BHF-UCL
  • positive regulation of fibroblast proliferation Source: BHF-UCL
  • positive regulation of lipopolysaccharide-mediated signaling pathway Source: BHF-UCL
  • positive regulation of MAP kinase activity Source: BHF-UCL
  • positive regulation of myeloid leukocyte cytokine production involved in immune response Source: BHF-UCL
  • positive regulation of peptidyl-serine phosphorylation Source: BHF-UCL
  • positive regulation of peptidyl-tyrosine phosphorylation Source: BHF-UCL
  • positive regulation of phosphorylation Source: MGI
  • positive regulation of prostaglandin secretion involved in immune response Source: BHF-UCL
  • positive regulation of protein kinase A signaling Source: MGI
  • positive regulation of protein phosphorylation Source: BHF-UCL
  • prostaglandin biosynthetic process Source: MGI
  • protein homotrimerization Source: MGI
  • regulation of cell proliferation Source: MGI
Complete GO annotation...

Keywords - Molecular functioni

Cytokine, Isomerase

Keywords - Biological processi

Immunity, Inflammatory response, Innate immunity

Enzyme and pathway databases

BRENDAi5.3.2.1. 3474.

Names & Taxonomyi

Protein namesi
Recommended name:
Macrophage migration inhibitory factor (EC:5.3.2.1)
Short name:
MIF
Alternative name(s):
Delayed early response protein 6
Short name:
DER6
Glycosylation-inhibiting factor
Short name:
GIF
L-dopachrome isomerase
L-dopachrome tautomerase (EC:5.3.3.12)
Phenylpyruvate tautomerase
Gene namesi
Name:Mif
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
ProteomesiUP000000589 Componenti: Chromosome 10

Organism-specific databases

MGIiMGI:96982. Mif.

Subcellular locationi

GO - Cellular componenti

  • cell surface Source: MGI
  • cytoplasm Source: MGI
  • extracellular exosome Source: MGI
  • extracellular region Source: MGI
  • extracellular space Source: BHF-UCL
  • myelin sheath Source: UniProtKB
  • nucleoplasm Source: MGI
  • vesicle Source: MGI
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Secreted

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi2 – 21P → G: Loss of tautomerase activity, reduced activation of intracellular signaling pathways, and reduced interaction with CXCR2 and COPS5. 2 Publications

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Initiator methioninei1 – 11Removed3 Publications
Chaini2 – 115114Macrophage migration inhibitory factorPRO_0000158066Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei78 – 781N6-acetyllysine; alternate1 Publication
Modified residuei78 – 781N6-succinyllysine; alternate1 Publication

Keywords - PTMi

Acetylation

Proteomic databases

MaxQBiP34884.
PaxDbiP34884.
PRIDEiP34884.

PTM databases

PhosphoSiteiP34884.

Expressioni

Gene expression databases

BgeeiP34884.
CleanExiMM_MIF.
ExpressionAtlasiP34884. baseline and differential.
GenevisibleiP34884. MM.

Interactioni

Subunit structurei

Homotrimer. Interacts with BNIPL (By similarity). Interacts with the CD74 extracellular domain. Interacts with COPS5 and with the CXCR2 extracellular domain.By similarity2 Publications

Protein-protein interaction databases

BioGridi201418. 1 interaction.
IntActiP34884. 4 interactions.
MINTiMINT-1869498.
STRINGi10090.ENSMUSP00000041149.

Structurei

Secondary structure

1
115
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Beta strandi3 – 108Combined sources
Helixi12 – 143Combined sources
Helixi19 – 3113Combined sources
Helixi35 – 373Combined sources
Beta strandi39 – 435Combined sources
Beta strandi47 – 504Combined sources
Beta strandi58 – 669Combined sources
Helixi70 – 8819Combined sources
Helixi92 – 943Combined sources
Beta strandi95 – 1017Combined sources
Helixi104 – 1063Combined sources
Beta strandi107 – 1093Combined sources

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
1MFFX-ray2.00A/B/C2-115[»]
1MFIX-ray1.80A/B/C2-115[»]
2GDGX-ray1.45A/B/C2-115[»]
ProteinModelPortaliP34884.
SMRiP34884. Positions 2-115.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP34884.

Family & Domainsi

Sequence similaritiesi

Belongs to the MIF family.Curated

Phylogenomic databases

eggNOGiNOG08790.
HOGENOMiHOG000112325.
HOVERGENiHBG003240.
InParanoidiP34884.
KOiK07253.
OMAiMGKPAQY.
OrthoDBiEOG7GXPDN.
PhylomeDBiP34884.
TreeFamiTF313853.

Family and domain databases

InterProiIPR001398. Macrophage_inhib_fac.
IPR019829. Macrophage_inhib_fac_CS.
IPR014347. Tautomerase/MIF_sf.
[Graphical view]
PANTHERiPTHR11954. PTHR11954. 1 hit.
PfamiPF01187. MIF. 1 hit.
[Graphical view]
ProDomiPD004816. Macrophage_inhib_fac. 1 hit.
[Graphical view] [Entries sharing at least one domain]
SUPFAMiSSF55331. SSF55331. 1 hit.
PROSITEiPS01158. MIF. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

P34884-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MPMFIVNTNV PRASVPEGFL SELTQQLAQA TGKPAQYIAV HVVPDQLMTF
60 70 80 90 100
SGTNDPCALC SLHSIGKIGG AQNRNYSKLL CGLLSDRLHI SPDRVYINYY
110
DMNAANVGWN GSTFA
Length:115
Mass (Da):12,504
Last modified:January 23, 2007 - v2
Checksum:i92D207B81B149945
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
Z23048 mRNA. Translation: CAA80583.1.
U19825 Genomic DNA. Translation: AAA91637.1.
L10613 mRNA. Translation: AAA37693.1.
U20156 Genomic DNA. Translation: AAA91638.1.
L39357 Genomic DNA. Translation: AAA74321.1.
BC024895 mRNA. Translation: AAH24895.1.
BC086928 mRNA. Translation: AAH86928.1.
L07607 mRNA. Translation: AAA37111.1.
CCDSiCCDS23934.1.
PIRiA44499.
RefSeqiNP_034928.1. NM_010798.2.
UniGeneiMm.2326.

Genome annotation databases

EnsembliENSMUST00000038169; ENSMUSP00000041149; ENSMUSG00000033307.
GeneIDi17319.
KEGGimmu:17319.
UCSCiuc007ftc.1. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
Z23048 mRNA. Translation: CAA80583.1.
U19825 Genomic DNA. Translation: AAA91637.1.
L10613 mRNA. Translation: AAA37693.1.
U20156 Genomic DNA. Translation: AAA91638.1.
L39357 Genomic DNA. Translation: AAA74321.1.
BC024895 mRNA. Translation: AAH24895.1.
BC086928 mRNA. Translation: AAH86928.1.
L07607 mRNA. Translation: AAA37111.1.
CCDSiCCDS23934.1.
PIRiA44499.
RefSeqiNP_034928.1. NM_010798.2.
UniGeneiMm.2326.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
1MFFX-ray2.00A/B/C2-115[»]
1MFIX-ray1.80A/B/C2-115[»]
2GDGX-ray1.45A/B/C2-115[»]
ProteinModelPortaliP34884.
SMRiP34884. Positions 2-115.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi201418. 1 interaction.
IntActiP34884. 4 interactions.
MINTiMINT-1869498.
STRINGi10090.ENSMUSP00000041149.

Chemistry

BindingDBiP34884.
ChEMBLiCHEMBL1926491.

PTM databases

PhosphoSiteiP34884.

Proteomic databases

MaxQBiP34884.
PaxDbiP34884.
PRIDEiP34884.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000038169; ENSMUSP00000041149; ENSMUSG00000033307.
GeneIDi17319.
KEGGimmu:17319.
UCSCiuc007ftc.1. mouse.

Organism-specific databases

CTDi4282.
MGIiMGI:96982. Mif.

Phylogenomic databases

eggNOGiNOG08790.
HOGENOMiHOG000112325.
HOVERGENiHBG003240.
InParanoidiP34884.
KOiK07253.
OMAiMGKPAQY.
OrthoDBiEOG7GXPDN.
PhylomeDBiP34884.
TreeFamiTF313853.

Enzyme and pathway databases

BRENDAi5.3.2.1. 3474.

Miscellaneous databases

EvolutionaryTraceiP34884.
NextBioi291888.
PROiP34884.
SOURCEiSearch...

Gene expression databases

BgeeiP34884.
CleanExiMM_MIF.
ExpressionAtlasiP34884. baseline and differential.
GenevisibleiP34884. MM.

Family and domain databases

InterProiIPR001398. Macrophage_inhib_fac.
IPR019829. Macrophage_inhib_fac_CS.
IPR014347. Tautomerase/MIF_sf.
[Graphical view]
PANTHERiPTHR11954. PTHR11954. 1 hit.
PfamiPF01187. MIF. 1 hit.
[Graphical view]
ProDomiPD004816. Macrophage_inhib_fac. 1 hit.
[Graphical view] [Entries sharing at least one domain]
SUPFAMiSSF55331. SSF55331. 1 hit.
PROSITEiPS01158. MIF. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. "MIF is a pituitary-derived cytokine that potentiates lethal endotoxaemia."
    Bernhagen J., Calandra T., Mitchell R.A., Martin S.B., Tracey K.J., Voelter W., Manogue K.R., Cerami A., Bucala R.
    Nature 365:756-759(1993) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 2-28.
    Tissue: Pituitary.
  2. "Growth factor-induced delayed early response genes."
    Lanahan A.A., Williams J.B., Sanders L.K., Nathans D.
    Mol. Cell. Biol. 12:3919-3929(1992) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA].
    Strain: BALB/c.
  3. "Molecular cloning and functional expression of a cDNA encoding glycosylation-inhibiting factor."
    Mikayama T., Nakano T., Gomi H., Nakagawa Y., Liu Y.C., Iwamatsu A., Weiser W.Y., Ishizaka K., Sato M., Ishii Y.
    Proc. Natl. Acad. Sci. U.S.A. 90:10056-10060(1993) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA], SUBCELLULAR LOCATION.
  4. "Cloning and characterization of the gene for mouse macrophage migration inhibitory factor (MIF)."
    Mitchell R., Bacher M., Bernhagen J., Pushkarskaya T., Seldin M.F., Bucala R.
    J. Immunol. 154:3863-3870(1995) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
    Strain: 129/Sv.
  5. "Structural characterization and chromosomal location of the mouse macrophage migration inhibitory factor gene and pseudogenes."
    Bozza M., Kolakowski L.F. Jr., Jenkins N.A., Gilbert D.J., Copeland N.G., David J.R., Gerard C.
    Genomics 27:412-419(1995) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
    Strain: 129/Sv.
  6. "Genomic cloning of mouse MIF (macrophage inhibitory factor) and genetic mapping of the human and mouse expressed gene and nine mouse pseudogenes."
    Kozak C.A., Adamson M.C., Buckler C.E., Segovia L., Paralkar V., Wistow G.
    Genomics 27:405-411(1995) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
    Strain: 129/Sv.
  7. "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].
    Strain: FVB/N.
    Tissue: Kidney and Mammary gland.
  8. Lubec G., Klug S.
    Submitted (MAR-2007) to UniProtKB
    Cited for: PROTEIN SEQUENCE OF 2-12, IDENTIFICATION BY MASS SPECTROMETRY.
    Tissue: Hippocampus.
  9. "A macrophage migration inhibitory factor is expressed in the differentiating cells of the eye lens."
    Wistow G.J., Shaughnessy M., Lee D.C., Hodin J., Zelenka P.S.
    Proc. Natl. Acad. Sci. U.S.A. 90:1272-1275(1993) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 6-115.
    Tissue: Lens.
  10. "Purification, bioactivity, and secondary structure analysis of mouse and human macrophage migration inhibitory factor (MIF)."
    Bernhagen J., Mitchell R.A., Calandra T., Voelter W., Cerami A., Bucala R.
    Biochemistry 33:14144-14155(1994) [PubMed] [Europe PMC] [Abstract]
    Cited for: CHARACTERIZATION.
  11. "Alternative chemical modifications reverse the binding orientation of a pharmacophore scaffold in the active site of macrophage migration inhibitory factor."
    Crichlow G.V., Cheng K.F., Dabideen D., Ochani M., Aljabari B., Pavlov V.A., Miller E.J., Lolis E., Al-Abed Y.
    J. Biol. Chem. 282:23089-23095(2007) [PubMed] [Europe PMC] [Abstract]
    Cited for: SUBCELLULAR LOCATION, ROLE OF TAUTOMERASE INHIBITORS IN IMPROVED SURVIVAL IN CASE OF SEPSIS.
  12. "A tautomerase-null macrophage migration-inhibitory factor (MIF) gene knock-in mouse model reveals that protein interactions and not enzymatic activity mediate MIF-dependent growth regulation."
    Fingerle-Rowson G., Kaleswarapu D.R., Schlander C., Kabgani N., Brocks T., Reinart N., Busch R., Schuetz A., Lue H., Du X., Liu A., Xiong H., Chen Y., Nemajerova A., Hallek M., Bernhagen J., Leng L., Bucala R.
    Mol. Cell. Biol. 29:1922-1932(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH CD74; CXCR2 AND COPS5, CATALYTIC ACTIVITY, MUTAGENESIS OF PRO-2.
  13. "SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways."
    Park J., Chen Y., Tishkoff D.X., Peng C., Tan M., Dai L., Xie Z., Zhang Y., Zwaans B.M., Skinner M.E., Lombard D.B., Zhao Y.
    Mol. Cell 50:919-930(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-78, SUCCINYLATION [LARGE SCALE ANALYSIS] AT LYS-78, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    Tissue: Embryonic fibroblast.
  14. "Crystal structure of macrophage migration inhibitory factor complexed with (E)-2-fluoro-p-hydroxycinnamate at 1.8 A resolution: implications for enzymatic catalysis and inhibition."
    Taylor A.B., Johnson W.H. Jr., Czerwinski R.M., Li H.S., Hackert M.L., Whitman C.P.
    Biochemistry 38:7444-7452(1999) [PubMed] [Europe PMC] [Abstract]
    Cited for: X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS).
  15. "Mechanism of the phenylpyruvate tautomerase activity of macrophage migration inhibitory factor: properties of the P1G, P1A, Y95F, and N97A mutants."
    Stamps S.L., Taylor A.B., Wang S.C., Hackert M.L., Whitman C.P.
    Biochemistry 39:9671-9678(2000) [PubMed] [Europe PMC] [Abstract]
    Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS), TAUTOMERASE ACTIVITY, IDENTIFICATION BY MASS SPECTROMETRY, CLEAVAGE OF INITIATOR METHIONINE, MUTAGENESIS OF PRO-2.
  16. "Inactivation of the phenylpyruvate tautomerase activity of macrophage migration inhibitory factor by 2-oxo-4-phenyl-3-butynoate."
    Golubkov P.A., Johnson W.H. Jr., Czerwinski R.M., Person M.D., Wang S.C., Whitman C.P., Hackert M.L.
    Bioorg. Chem. 34:183-199(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: X-RAY CRYSTALLOGRAPHY (1.45 ANGSTROMS) IN COMPLEX WITH INHIBITOR, TAUTOMERASE ACTIVITY, IDENTIFICATION BY MASS SPECTROMETRY, SUBUNIT.

Entry informationi

Entry nameiMIF_MOUSE
AccessioniPrimary (citable) accession number: P34884
Entry historyi
Integrated into UniProtKB/Swiss-Prot: February 1, 1994
Last sequence update: January 23, 2007
Last modified: June 24, 2015
This is version 142 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Miscellaneous

MIF tautomerase inhibitors improve survival in case of sepsis.

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  3. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.