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Protein

HLA class II histocompatibility antigen gamma chain

Gene

CD74

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Plays a critical role in MHC class II antigen processing by stabilizing peptide-free class II alpha/beta heterodimers in a complex soon after their synthesis and directing transport of the complex from the endoplasmic reticulum to the endosomal/lysosomal system where the antigen processing and binding of antigenic peptides to MHC class II takes place. Serves as cell surface receptor for the cytokine MIF.

GO - Molecular functioni

  • beta-amyloid binding Source: BHF-UCL
  • cytokine binding Source: UniProtKB
  • cytokine receptor activity Source: BHF-UCL
  • identical protein binding Source: UniProtKB
  • macrophage migration inhibitory factor binding Source: BHF-UCL
  • MHC class II protein binding Source: UniProtKB
  • MHC class II protein binding, via antigen binding groove Source: UniProtKB
  • MHC class II protein complex binding Source: UniProtKB
  • protein binding involved in protein folding Source: UniProtKB

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Chaperone

Keywords - Biological processi

Adaptive immunity, Immunity

Enzyme and pathway databases

BioCyciZFISH:ENSG00000019582-MONOMER.
ReactomeiR-HSA-202733. Cell surface interactions at the vascular wall.
R-HSA-2132295. MHC class II antigen presentation.
SIGNORiP04233.

Protein family/group databases

MEROPSiI31.002.

Names & Taxonomyi

Protein namesi
Recommended name:
HLA class II histocompatibility antigen gamma chain
Alternative name(s):
HLA-DR antigens-associated invariant chain
Ia antigen-associated invariant chain
Short name:
Ii
p33
CD_antigen: CD74
Gene namesi
Name:CD74
Synonyms:DHLAG
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 5

Organism-specific databases

HGNCiHGNC:1697. CD74.

Subcellular locationi

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini1 – 46CytoplasmicSequence analysisAdd BLAST46
Transmembranei47 – 72Helical; Signal-anchor for type II membrane proteinSequence analysisAdd BLAST26
Topological domaini73 – 296ExtracellularSequence analysisAdd BLAST224

GO - Cellular componenti

  • cell surface Source: BHF-UCL
  • clathrin-coated endocytic vesicle membrane Source: Reactome
  • endocytic vesicle membrane Source: Reactome
  • ER to Golgi transport vesicle membrane Source: Reactome
  • external side of plasma membrane Source: Ensembl
  • extracellular exosome Source: UniProtKB
  • Golgi membrane Source: Reactome
  • integral component of lumenal side of endoplasmic reticulum membrane Source: Reactome
  • integral component of membrane Source: BHF-UCL
  • intracellular Source: UniProtKB
  • lysosomal lumen Source: Reactome
  • lysosomal membrane Source: Reactome
  • macrophage migration inhibitory factor receptor complex Source: BHF-UCL
  • membrane Source: UniProtKB
  • MHC class II protein complex Source: Ensembl
  • multivesicular body Source: Ensembl
  • NOS2-CD74 complex Source: Ensembl
  • plasma membrane Source: Reactome
  • trans-Golgi network membrane Source: Reactome
  • transport vesicle membrane Source: Reactome
  • vacuole Source: BHF-UCL
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Endoplasmic reticulum, Endosome, Golgi apparatus, Lysosome, Membrane

Pathology & Biotechi

Involvement in diseasei

A chromosomal aberration involving CD74 is found in a non-small cell lung tumor. Results in the formation of a CD74-ROS1 chimeric protein.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei208 – 209Breakpoint for translocation to form a CD74-ROS1 fusion protein2

Organism-specific databases

DisGeNETi972.
OpenTargetsiENSG00000019582.
PharmGKBiPA26236.

Chemistry databases

ChEMBLiCHEMBL4692.
GuidetoPHARMACOLOGYi2840.

Polymorphism and mutation databases

BioMutaiCD74.
DMDMi20178292.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000679541 – 296HLA class II histocompatibility antigen gamma chainAdd BLAST296

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei25PhosphoserineBy similarity1
Glycosylationi130N-linked (GlcNAc...)1
Glycosylationi136N-linked (GlcNAc...)1 Publication1
Glycosylationi203O-linked (GalNAc...)2 Publications1
Disulfide bondi213 ↔ 232PROSITE-ProRule annotation1 Publication
Disulfide bondi243 ↔ 250PROSITE-ProRule annotation1 Publication
Disulfide bondi252 ↔ 271PROSITE-ProRule annotation1 Publication
Glycosylationi256N-linked (GlcNAc...)1 Publication1
Glycosylationi281O-linked (GalNAc...)1 Publication1

Post-translational modificationi

N- and O-glycosylated. O-glycosylated with core 1 or possibly core 8 glycans.4 Publications

Keywords - PTMi

Disulfide bond, Glycoprotein, Phosphoprotein, Proteoglycan

Proteomic databases

EPDiP04233.
MaxQBiP04233.
PaxDbiP04233.
PeptideAtlasiP04233.
PRIDEiP04233.

PTM databases

iPTMnetiP04233.
PhosphoSitePlusiP04233.
SwissPalmiP04233.
UniCarbKBiP04233.

Miscellaneous databases

PMAP-CutDBP04233.

Expressioni

Gene expression databases

BgeeiENSG00000019582.
CleanExiHS_CD74.
ExpressionAtlasiP04233. baseline and differential.
GenevisibleiP04233. HS.

Organism-specific databases

HPAiCAB002506.
HPA010592.

Interactioni

Subunit structurei

Homotrimer. In the endoplasmic reticulum (ER) it forms a heterononameric MHC II-Ii complex: 3 MHC class II molecules (heterodimers of an alpha and a beta subunit) bind to the CD74 homotrimer (also known as invariant chain or HLA class II histocompatibility antigen gamma chain). In the endosomal/lysosomal system, the CD74 component undergoes sequential degradation by various proteases, including CTSS and CTSL, leaving a small fragment termed CLIP (class-II-associated invariant chain peptide) attached to the MHC class II molecule (alpha-beta-CLIP complex). This processed complex interacts with HLA_DM and HLA_DO heterodimers in order to release CLIP and facilitate the binding of antigenic peptides to the MHC class II molecules.2 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
CXCR4P610734EBI-2622890,EBI-489411

GO - Molecular functioni

  • cytokine binding Source: UniProtKB
  • identical protein binding Source: UniProtKB
  • macrophage migration inhibitory factor binding Source: BHF-UCL
  • MHC class II protein binding Source: UniProtKB
  • MHC class II protein binding, via antigen binding groove Source: UniProtKB
  • MHC class II protein complex binding Source: UniProtKB
  • protein binding involved in protein folding Source: UniProtKB

Protein-protein interaction databases

BioGridi107410. 12 interactors.
IntActiP04233. 61 interactors.
MINTiMINT-1488574.
STRINGi9606.ENSP00000009530.

Chemistry databases

BindingDBiP04233.

Structurei

Secondary structure

1296
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi139 – 149Combined sources11
Helixi162 – 172Combined sources11
Helixi175 – 194Combined sources20
Helixi212 – 217Combined sources6
Beta strandi236 – 238Combined sources3
Beta strandi240 – 244Combined sources5
Turni245 – 248Combined sources4
Beta strandi249 – 253Combined sources5
Beta strandi265 – 267Combined sources3

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1A6AX-ray2.75C103-117[»]
1ICFX-ray2.00I/J210-274[»]
1IIENMR-A/B/C134-208[»]
1L3HNMR-A210-274[»]
1MUJX-ray2.15C97-121[»]
3PDOX-ray1.95C102-120[»]
3PGCX-ray2.66C/F106-120[»]
3PGDX-ray2.72C/F106-120[»]
3QXAX-ray2.71C/F103-117[»]
3QXDX-ray2.30C/F103-117[»]
4AENX-ray2.20C106-120[»]
4AH2X-ray2.36B106-120[»]
4X5WX-ray1.34C102-120[»]
ProteinModelPortaliP04233.
SMRiP04233.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP04233.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini210 – 271Thyroglobulin type-1PROSITE-ProRule annotationAdd BLAST62

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni103 – 117CLIPAdd BLAST15

Sequence similaritiesi

Contains 1 thyroglobulin type-1 domain.PROSITE-ProRule annotation

Keywords - Domaini

Signal-anchor, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiENOG410IMYW. Eukaryota.
ENOG410Z4PR. LUCA.
GeneTreeiENSGT00390000008961.
HOVERGENiHBG004444.
InParanoidiP04233.
KOiK06505.
PhylomeDBiP04233.
TreeFamiTF317779.

Family and domain databases

Gene3Di1.10.870.10. 1 hit.
4.10.800.10. 1 hit.
InterProiIPR015386. MHC_II-assoc_invar/CLIP_MHC-bd.
IPR022339. MHC_II-assoc_invar_chain.
IPR011988. MHC_II-assoc_invariant_trimer.
IPR000716. Thyroglobulin_1.
[Graphical view]
PfamiPF09307. MHC2-interact. 1 hit.
PF08831. MHCassoc_trimer. 1 hit.
PF00086. Thyroglobulin_1. 1 hit.
[Graphical view]
PIRSFiPIRSF001992. CD74_antigen. 1 hit.
PRINTSiPR01990. CD74ANTIGEN.
SMARTiSM00211. TY. 1 hit.
[Graphical view]
SUPFAMiSSF48305. SSF48305. 1 hit.
SSF57610. SSF57610. 1 hit.
PROSITEiPS00484. THYROGLOBULIN_1_1. 1 hit.
PS51162. THYROGLOBULIN_1_2. 1 hit.
[Graphical view]

Sequences (3)i

Sequence statusi: Complete.

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: P04233-1) [UniParc]FASTAAdd to basket
Also known as: Long

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.

« Hide

        10         20         30         40         50
MHRRRSRSCR EDQKPVMDDQ RDLISNNEQL PMLGRRPGAP ESKCSRGALY
60 70 80 90 100
TGFSILVTLL LAGQATTAYF LYQQQGRLDK LTVTSQNLQL ENLRMKLPKP
110 120 130 140 150
PKPVSKMRMA TPLLMQALPM GALPQGPMQN ATKYGNMTED HVMHLLQNAD
160 170 180 190 200
PLKVYPPLKG SFPENLRHLK NTMETIDWKV FESWMHHWLL FEMSRHSLEQ
210 220 230 240 250
KPTDAPPKVL TKCQEEVSHI PAVHPGSFRP KCDENGNYLP LQCYGSIGYC
260 270 280 290
WCVFPNGTEV PNTRSRGHHN CSESLELEDP SSGLGVTKQD LGPVPM
Length:296
Mass (Da):33,516
Last modified:April 16, 2002 - v3
Checksum:i27A13F252D5FB91D
GO
Isoform 2 (identifier: P04233-2) [UniParc]FASTAAdd to basket
Also known as: Short

The sequence of this isoform differs from the canonical sequence as follows:
     209-272: Missing.

Show »
Length:232
Mass (Da):26,399
Checksum:i5144439D0FD27C99
GO
Isoform 3 (identifier: P04233-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     148-160: NADPLKVYPPLKG → SHWNWRTRLLGWV
     161-296: Missing.

Show »
Length:160
Mass (Da):18,328
Checksum:i95CB3D7226497DE8
GO

Sequence cautioni

The sequence AAA36304 differs from that shown. Reason: Erroneous initiation.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti167R → T in CAA27047 (PubMed:3001652).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_037869148 – 160NADPL…PPLKG → SHWNWRTRLLGWV in isoform 3. 1 PublicationAdd BLAST13
Alternative sequenceiVSP_037870161 – 296Missing in isoform 3. 1 PublicationAdd BLAST136
Alternative sequenceiVSP_005331209 – 272Missing in isoform 2. 5 PublicationsAdd BLAST64

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
K01144 mRNA. Translation: AAA36304.1. Different initiation.
X00497 mRNA. Translation: CAA25192.1.
X00497 mRNA. Translation: CAA25193.1.
X03339 Genomic DNA. Translation: CAA27046.1.
X03340 Genomic DNA. Translation: CAA27047.1.
M13560
, M13555, M13556, M13558, M13559 Genomic DNA. Translation: AAA36033.1.
BT019505 mRNA. Translation: AAV38312.1.
AK292076 mRNA. Translation: BAF84765.1.
AK297889 mRNA. Translation: BAG60210.1.
AC011372 Genomic DNA. No translation available.
AC011388 Genomic DNA. No translation available.
CH471062 Genomic DNA. Translation: EAW61727.1.
CH471062 Genomic DNA. Translation: EAW61728.1.
CH471062 Genomic DNA. Translation: EAW61729.1.
CH471062 Genomic DNA. Translation: EAW61730.1.
CH471062 Genomic DNA. Translation: EAW61731.1.
BC018726 mRNA. Translation: AAH18726.1.
BC024272 mRNA. Translation: AAH24272.1.
CCDSiCCDS34276.1. [P04233-3]
CCDS47308.1. [P04233-2]
CCDS47309.1. [P04233-1]
PIRiA93981. HLHUG.
RefSeqiNP_001020329.1. NM_001025158.2. [P04233-3]
NP_001020330.1. NM_001025159.2. [P04233-1]
NP_004346.1. NM_004355.3. [P04233-2]
UniGeneiHs.436568.

Genome annotation databases

EnsembliENST00000009530; ENSP00000009530; ENSG00000019582. [P04233-1]
ENST00000353334; ENSP00000230685; ENSG00000019582. [P04233-2]
ENST00000377795; ENSP00000367026; ENSG00000019582. [P04233-3]
GeneIDi972.
KEGGihsa:972.
UCSCiuc003lsc.4. human. [P04233-1]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
K01144 mRNA. Translation: AAA36304.1. Different initiation.
X00497 mRNA. Translation: CAA25192.1.
X00497 mRNA. Translation: CAA25193.1.
X03339 Genomic DNA. Translation: CAA27046.1.
X03340 Genomic DNA. Translation: CAA27047.1.
M13560
, M13555, M13556, M13558, M13559 Genomic DNA. Translation: AAA36033.1.
BT019505 mRNA. Translation: AAV38312.1.
AK292076 mRNA. Translation: BAF84765.1.
AK297889 mRNA. Translation: BAG60210.1.
AC011372 Genomic DNA. No translation available.
AC011388 Genomic DNA. No translation available.
CH471062 Genomic DNA. Translation: EAW61727.1.
CH471062 Genomic DNA. Translation: EAW61728.1.
CH471062 Genomic DNA. Translation: EAW61729.1.
CH471062 Genomic DNA. Translation: EAW61730.1.
CH471062 Genomic DNA. Translation: EAW61731.1.
BC018726 mRNA. Translation: AAH18726.1.
BC024272 mRNA. Translation: AAH24272.1.
CCDSiCCDS34276.1. [P04233-3]
CCDS47308.1. [P04233-2]
CCDS47309.1. [P04233-1]
PIRiA93981. HLHUG.
RefSeqiNP_001020329.1. NM_001025158.2. [P04233-3]
NP_001020330.1. NM_001025159.2. [P04233-1]
NP_004346.1. NM_004355.3. [P04233-2]
UniGeneiHs.436568.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1A6AX-ray2.75C103-117[»]
1ICFX-ray2.00I/J210-274[»]
1IIENMR-A/B/C134-208[»]
1L3HNMR-A210-274[»]
1MUJX-ray2.15C97-121[»]
3PDOX-ray1.95C102-120[»]
3PGCX-ray2.66C/F106-120[»]
3PGDX-ray2.72C/F106-120[»]
3QXAX-ray2.71C/F103-117[»]
3QXDX-ray2.30C/F103-117[»]
4AENX-ray2.20C106-120[»]
4AH2X-ray2.36B106-120[»]
4X5WX-ray1.34C102-120[»]
ProteinModelPortaliP04233.
SMRiP04233.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi107410. 12 interactors.
IntActiP04233. 61 interactors.
MINTiMINT-1488574.
STRINGi9606.ENSP00000009530.

Chemistry databases

BindingDBiP04233.
ChEMBLiCHEMBL4692.
GuidetoPHARMACOLOGYi2840.

Protein family/group databases

MEROPSiI31.002.

PTM databases

iPTMnetiP04233.
PhosphoSitePlusiP04233.
SwissPalmiP04233.
UniCarbKBiP04233.

Polymorphism and mutation databases

BioMutaiCD74.
DMDMi20178292.

Proteomic databases

EPDiP04233.
MaxQBiP04233.
PaxDbiP04233.
PeptideAtlasiP04233.
PRIDEiP04233.

Protocols and materials databases

DNASUi972.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000009530; ENSP00000009530; ENSG00000019582. [P04233-1]
ENST00000353334; ENSP00000230685; ENSG00000019582. [P04233-2]
ENST00000377795; ENSP00000367026; ENSG00000019582. [P04233-3]
GeneIDi972.
KEGGihsa:972.
UCSCiuc003lsc.4. human. [P04233-1]

Organism-specific databases

CTDi972.
DisGeNETi972.
GeneCardsiCD74.
HGNCiHGNC:1697. CD74.
HPAiCAB002506.
HPA010592.
MIMi142790. gene.
neXtProtiNX_P04233.
OpenTargetsiENSG00000019582.
PharmGKBiPA26236.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiENOG410IMYW. Eukaryota.
ENOG410Z4PR. LUCA.
GeneTreeiENSGT00390000008961.
HOVERGENiHBG004444.
InParanoidiP04233.
KOiK06505.
PhylomeDBiP04233.
TreeFamiTF317779.

Enzyme and pathway databases

BioCyciZFISH:ENSG00000019582-MONOMER.
ReactomeiR-HSA-202733. Cell surface interactions at the vascular wall.
R-HSA-2132295. MHC class II antigen presentation.
SIGNORiP04233.

Miscellaneous databases

ChiTaRSiCD74. human.
EvolutionaryTraceiP04233.
GeneWikiiCD74.
GenomeRNAii972.
PMAP-CutDBP04233.
PROiP04233.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000019582.
CleanExiHS_CD74.
ExpressionAtlasiP04233. baseline and differential.
GenevisibleiP04233. HS.

Family and domain databases

Gene3Di1.10.870.10. 1 hit.
4.10.800.10. 1 hit.
InterProiIPR015386. MHC_II-assoc_invar/CLIP_MHC-bd.
IPR022339. MHC_II-assoc_invar_chain.
IPR011988. MHC_II-assoc_invariant_trimer.
IPR000716. Thyroglobulin_1.
[Graphical view]
PfamiPF09307. MHC2-interact. 1 hit.
PF08831. MHCassoc_trimer. 1 hit.
PF00086. Thyroglobulin_1. 1 hit.
[Graphical view]
PIRSFiPIRSF001992. CD74_antigen. 1 hit.
PRINTSiPR01990. CD74ANTIGEN.
SMARTiSM00211. TY. 1 hit.
[Graphical view]
SUPFAMiSSF48305. SSF48305. 1 hit.
SSF57610. SSF57610. 1 hit.
PROSITEiPS00484. THYROGLOBULIN_1_1. 1 hit.
PS51162. THYROGLOBULIN_1_2. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiHG2A_HUMAN
AccessioniPrimary (citable) accession number: P04233
Secondary accession number(s): A8K7R1
, B4DNE8, D3DQG3, D3DQG4, Q14597, Q29832, Q5U0J8, Q8SNA0, Q8WLP6
Entry historyi
Integrated into UniProtKB/Swiss-Prot: March 20, 1987
Last sequence update: April 16, 2002
Last modified: November 30, 2016
This is version 193 of the entry and version 3 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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.

Miscellaneousi

Keywords - Technical termi

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

Documents

  1. Human cell differentiation molecules
    CD nomenclature of surface proteins of human leucocytes and list of entries
  2. Human chromosome 5
    Human chromosome 5: entries, gene names and cross-references to MIM
  3. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  4. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  5. SIMILARITY comments
    Index of protein domains and families

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 one 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.