UniProtKB - P04233 (HG2A_HUMAN)
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Protein
HLA class II histocompatibility antigen gamma chain
Gene
CD74
Organism
Homo sapiens (Human)
Status
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
- CD4 receptor binding Source: CAFA
- 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: BHF-UCL
- MHC class II protein binding, via antigen binding groove Source: UniProtKB
- MHC class II protein complex binding Source: UniProtKB
- nitric-oxide synthase binding Source: Ensembl
- protein binding involved in protein folding Source: UniProtKB
GO - Biological processi
- activation of MAPK activity Source: Ensembl
- antigen processing and presentation of endogenous antigen Source: UniProtKB
- antigen processing and presentation of exogenous peptide antigen via MHC class II Source: Reactome
- cell proliferation Source: UniProtKB
- chaperone mediated protein folding requiring cofactor Source: Ensembl
- defense response Source: Ensembl
- immunoglobulin mediated immune response Source: UniProtKB
- intracellular protein transport Source: UniProtKB
- leukocyte migration Source: Reactome
- macrophage migration inhibitory factor signaling pathway Source: Ensembl
- negative regulation of apoptotic process Source: UniProtKB
- negative regulation of DNA damage response, signal transduction by p53 class mediator Source: BHF-UCL
- negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator Source: BHF-UCL
- negative regulation of mature B cell apoptotic process Source: Ensembl
- negative regulation of peptide secretion Source: BHF-UCL
- negative regulation of T cell differentiation Source: Ensembl
- negative thymic T cell selection Source: Ensembl
- positive regulation of B cell proliferation Source: BHF-UCL
- positive regulation of chemokine (C-X-C motif) ligand 2 production Source: BHF-UCL
- positive regulation of cytokine-mediated signaling pathway Source: BHF-UCL
- positive regulation of dendritic cell antigen processing and presentation Source: Ensembl
- positive regulation of ERK1 and ERK2 cascade Source: BHF-UCL
- positive regulation of fibroblast proliferation Source: BHF-UCL
- positive regulation of I-kappaB kinase/NF-kappaB signaling Source: CAFA
- positive regulation of kinase activity Source: CAFA
- positive regulation of macrophage cytokine production Source: BHF-UCL
- positive regulation of MAPK cascade Source: CAFA
- positive regulation of monocyte differentiation Source: CAFA
- positive regulation of neutrophil chemotaxis Source: BHF-UCL
- positive regulation of peptidyl-tyrosine phosphorylation Source: BHF-UCL
- positive regulation of protein phosphorylation Source: CAFA
- positive regulation of T cell differentiation Source: Ensembl
- positive regulation of transcription, DNA-templated Source: CAFA
- positive regulation of type 2 immune response Source: Ensembl
- positive regulation of viral entry into host cell Source: CAFA
- positive thymic T cell selection Source: Ensembl
- prostaglandin biosynthetic process Source: UniProtKB
- protein complex assembly Source: UniProtKB
- protein heterotetramerization Source: CAFA
- regulation of macrophage activation Source: UniProtKB
- signal transduction Source: UniProtKB
- T cell selection Source: UniProtKB
Keywordsi
| Molecular function | Chaperone |
| Biological process | Adaptive immunity, Immunity |
Enzyme and pathway databases
| Reactomei | R-HSA-202733. Cell surface interactions at the vascular wall. R-HSA-2132295. MHC class II antigen presentation. |
| SIGNORi | P04233. |
Protein family/group databases
| MEROPSi | I31.002. |
Names & Taxonomyi
| Protein namesi | Recommended name: HLA class II histocompatibility antigen gamma chainAlternative 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 |
| Organismi | Homo sapiens (Human) |
| Taxonomic identifieri | 9606 [NCBI] |
| Taxonomic lineagei | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo |
| Proteomesi |
|
Organism-specific databases
| HGNCi | HGNC:1697. CD74. |
Subcellular locationi
- Cell membrane Curated; Single-pass type II membrane protein Curated
- Endoplasmic reticulum membrane
- Golgi apparatus › trans-Golgi network
- Endosome
- Lysosome
Note: Transits through a number of intracellular compartments in the endocytic pathway. It can either undergo proteolysis or reach the cell membrane.
Topology
| Feature key | Position(s) | DescriptionActions | Graphical view | Length |
|---|---|---|---|---|
| Topological domaini | 1 – 46 | CytoplasmicSequence analysisAdd BLAST | 46 | |
| Transmembranei | 47 – 72 | Helical; Signal-anchor for type II membrane proteinSequence analysisAdd BLAST | 26 | |
| Topological domaini | 73 – 296 | ExtracellularSequence analysisAdd BLAST | 224 |
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
Keywords - Cellular componenti
Cell membrane, Endoplasmic reticulum, Endosome, Golgi apparatus, Lysosome, MembranePathology & 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.1 Publication
Sites
| Feature key | Position(s) | DescriptionActions | Graphical view | Length |
|---|---|---|---|---|
| Sitei | 208 – 209 | Breakpoint for translocation to form a CD74-ROS1 fusion protein | 2 |
Organism-specific databases
| DisGeNETi | 972. |
| OpenTargetsi | ENSG00000019582. |
| PharmGKBi | PA26236. |
Chemistry databases
| ChEMBLi | CHEMBL4692. |
| GuidetoPHARMACOLOGYi | 2840. |
Polymorphism and mutation databases
| BioMutai | CD74. |
| DMDMi | 20178292. |
PTM / Processingi
Molecule processing
| Feature key | Position(s) | DescriptionActions | Graphical view | Length |
|---|---|---|---|---|
| ChainiPRO_0000067954 | 1 – 296 | HLA class II histocompatibility antigen gamma chainAdd BLAST | 296 |
Amino acid modifications
| Feature key | Position(s) | DescriptionActions | Graphical view | Length |
|---|---|---|---|---|
| Modified residuei | 25 | PhosphoserineBy similarity | 1 | |
| Glycosylationi | 130 | N-linked (GlcNAc...) asparagine | 1 | |
| Glycosylationi | 136 | N-linked (GlcNAc...) asparagine1 Publication | 1 | |
| Glycosylationi | 203 | O-linked (GalNAc...) threonine2 Publications | 1 | |
| Disulfide bondi | 213 ↔ 232 | PROSITE-ProRule annotation1 Publication | ||
| Disulfide bondi | 243 ↔ 250 | PROSITE-ProRule annotation1 Publication | ||
| Disulfide bondi | 252 ↔ 271 | PROSITE-ProRule annotation1 Publication | ||
| Glycosylationi | 256 | N-linked (GlcNAc...) asparagine1 Publication | 1 | |
| Glycosylationi | 281 | O-linked (GalNAc...) serine1 Publication | 1 |
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, ProteoglycanProteomic databases
| EPDi | P04233. |
| MaxQBi | P04233. |
| PaxDbi | P04233. |
| PeptideAtlasi | P04233. |
| PRIDEi | P04233. |
PTM databases
| iPTMneti | P04233. |
| PhosphoSitePlusi | P04233. |
| SwissPalmi | P04233. |
| UniCarbKBi | P04233. |
Miscellaneous databases
| PMAP-CutDBi | P04233. |
Expressioni
Gene expression databases
| Bgeei | ENSG00000019582. |
| CleanExi | HS_CD74. |
| ExpressionAtlasi | P04233. baseline and differential. |
| Genevisiblei | P04233. HS. |
Organism-specific databases
| HPAi | CAB002506. 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
| With | Entry | #Exp. | IntAct | Notes |
|---|---|---|---|---|
| CXCR4 | P61073 | 4 | EBI-2622890,EBI-489411 |
GO - Molecular functioni
- CD4 receptor binding Source: CAFA
- cytokine binding Source: UniProtKB
- identical protein binding Source: UniProtKB
- macrophage migration inhibitory factor binding Source: BHF-UCL
- MHC class II protein binding Source: BHF-UCL
- MHC class II protein binding, via antigen binding groove Source: UniProtKB
- MHC class II protein complex binding Source: UniProtKB
- nitric-oxide synthase binding Source: Ensembl
- protein binding involved in protein folding Source: UniProtKB
Protein-protein interaction databases
| BioGridi | 107410. 12 interactors. |
| IntActi | P04233. 87 interactors. |
| MINTi | MINT-1488574. |
| STRINGi | 9606.ENSP00000009530. |
Chemistry databases
| BindingDBi | P04233. |
Structurei
Secondary structure
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details| Feature key | Position(s) | DescriptionActions | Graphical view | Length |
|---|---|---|---|---|
| Helixi | 139 – 149 | Combined sources | 11 | |
| Helixi | 162 – 172 | Combined sources | 11 | |
| Helixi | 175 – 194 | Combined sources | 20 | |
| Helixi | 212 – 217 | Combined sources | 6 | |
| Beta strandi | 236 – 238 | Combined sources | 3 | |
| Beta strandi | 240 – 244 | Combined sources | 5 | |
| Turni | 245 – 248 | Combined sources | 4 | |
| Beta strandi | 249 – 253 | Combined sources | 5 | |
| Beta strandi | 265 – 267 | Combined sources | 3 |
3D structure databases
| Select the link destinations: PDBei RCSB PDBi PDBji Links Updated | PDB entry | Method | Resolution (Å) | Chain | Positions | PDBsum |
| 1A6A | X-ray | 2.75 | C | 103-117 | [»] | |
| 1ICF | X-ray | 2.00 | I/J | 210-274 | [»] | |
| 1IIE | NMR | - | A/B/C | 134-208 | [»] | |
| 1L3H | NMR | - | A | 210-274 | [»] | |
| 1MUJ | X-ray | 2.15 | C | 97-121 | [»] | |
| 3PDO | X-ray | 1.95 | C | 102-120 | [»] | |
| 3PGC | X-ray | 2.66 | C/F | 106-120 | [»] | |
| 3PGD | X-ray | 2.72 | C/F | 106-120 | [»] | |
| 3QXA | X-ray | 2.71 | C/F | 103-117 | [»] | |
| 3QXD | X-ray | 2.30 | C/F | 103-117 | [»] | |
| 4AEN | X-ray | 2.20 | C | 106-120 | [»] | |
| 4AH2 | X-ray | 2.36 | B | 106-120 | [»] | |
| 4X5W | X-ray | 1.34 | C | 102-120 | [»] | |
| 5KSU | X-ray | 2.73 | C/F | 103-117 | [»] | |
| 5KSV | X-ray | 2.19 | C | 109-123 | [»] | |
| ProteinModelPortali | P04233. | |||||
| SMRi | P04233. | |||||
| ModBasei | Search... | |||||
| MobiDBi | Search... | |||||
Miscellaneous databases
| EvolutionaryTracei | P04233. |
Family & Domainsi
Domains and Repeats
| Feature key | Position(s) | DescriptionActions | Graphical view | Length |
|---|---|---|---|---|
| Domaini | 210 – 271 | Thyroglobulin type-1PROSITE-ProRule annotationAdd BLAST | 62 |
Region
| Feature key | Position(s) | DescriptionActions | Graphical view | Length |
|---|---|---|---|---|
| Regioni | 103 – 117 | CLIPAdd BLAST | 15 |
Keywords - Domaini
Signal-anchor, Transmembrane, Transmembrane helixPhylogenomic databases
| eggNOGi | ENOG410IMYW. Eukaryota. ENOG410Z4PR. LUCA. |
| GeneTreei | ENSGT00390000008961. |
| HOVERGENi | HBG004444. |
| InParanoidi | P04233. |
| KOi | K06505. |
| PhylomeDBi | P04233. |
| TreeFami | TF317779. |
Family and domain databases
| Gene3Di | 1.10.870.10. 1 hit. 4.10.800.10. 1 hit. |
| InterProi | View protein in InterPro IPR015386. MHC_II-assoc_invar/CLIP_MHC-bd. IPR022339. MHC_II-assoc_invar_chain. IPR011988. MHC_II-assoc_invariant_trimer. IPR000716. Thyroglobulin_1. |
| Pfami | View protein in Pfam PF09307. MHC2-interact. 1 hit. PF08831. MHCassoc_trimer. 1 hit. PF00086. Thyroglobulin_1. 1 hit. |
| PRINTSi | PR01990. CD74ANTIGEN. |
| SMARTi | View protein in SMART SM00211. TY. 1 hit. |
| SUPFAMi | SSF48305. SSF48305. 1 hit. SSF57610. SSF57610. 1 hit. |
| PROSITEi | View protein in PROSITE PS00484. THYROGLOBULIN_1_1. 1 hit. PS51162. THYROGLOBULIN_1_2. 1 hit. |
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.
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
Sequence cautioni
The sequence AAA36304 differs from that shown. Reason: Erroneous initiation.Curated
Experimental Info
| Feature key | Position(s) | DescriptionActions | Graphical view | Length |
|---|---|---|---|---|
| Sequence conflicti | 167 | R → T in CAA27047 (PubMed:3001652).Curated | 1 |
Alternative sequence
| Feature key | Position(s) | DescriptionActions | Graphical view | Length |
|---|---|---|---|---|
| Alternative sequenceiVSP_037869 | 148 – 160 | NADPL…PPLKG → SHWNWRTRLLGWV in isoform 3. 1 PublicationAdd BLAST | 13 | |
| Alternative sequenceiVSP_037870 | 161 – 296 | Missing in isoform 3. 1 PublicationAdd BLAST | 136 | |
| Alternative sequenceiVSP_005331 | 209 – 272 | Missing in isoform 2. 5 PublicationsAdd BLAST | 64 |
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 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. |
| CCDSi | CCDS34276.1. [P04233-3] CCDS47308.1. [P04233-2] CCDS47309.1. [P04233-1] |
| PIRi | A93981. HLHUG. |
| RefSeqi | NP_001020329.1. NM_001025158.2. [P04233-3] NP_001020330.1. NM_001025159.2. [P04233-1] NP_004346.1. NM_004355.3. [P04233-2] |
| UniGenei | Hs.436568. |
Genome annotation databases
| Ensembli | ENST00000009530; ENSP00000009530; ENSG00000019582. [P04233-1] ENST00000353334; ENSP00000230685; ENSG00000019582. [P04233-2] ENST00000377795; ENSP00000367026; ENSG00000019582. [P04233-3] |
| GeneIDi | 972. |
| KEGGi | hsa:972. |
| UCSCi | uc003lsc.4. human. [P04233-1] |
Keywords - Coding sequence diversityi
Alternative splicingSimilar 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. |
Entry informationi
| Entry namei | HG2A_HUMAN | |
| Accessioni | P04233Primary (citable) accession number: P04233 Secondary accession number(s): A8K7R1 Q8WLP6 | |
| Entry historyi | Integrated into UniProtKB/Swiss-Prot: | March 20, 1987 |
| Last sequence update: | April 16, 2002 | |
| Last modified: | June 7, 2017 | |
| This is version 197 of the entry and version 3 of the sequence. See complete history. | ||
| Entry statusi | 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. | |
Miscellaneousi
Keywords - Technical termi
3D-structure, Complete proteome, Direct protein sequencing, Reference proteomeDocuments
- Human cell differentiation molecules
CD nomenclature of surface proteins of human leucocytes and list of entries - Human chromosome 5
Human chromosome 5: entries, gene names and cross-references to MIM - MIM cross-references
Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot - PDB cross-references
Index of Protein Data Bank (PDB) cross-references
