Q95IE3 (2B1C_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
HLA class II histocompatibility antigen, DRB1-12 beta chain

Alternative name(s):
MHC class II antigen DRB1*12
Short name=DR-12
Short name=DR12

Gene names

Name:

HLA-DRB1

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	266 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	Binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells. The peptide binding cleft accommodates peptides of 10-30 residues. The peptides presented by MHC class II molecules are generated mostly by degradation of proteins that access the endocytic route, where they are processed by lysosomal proteases and other hydrolases. Exogenous antigens that have been endocytosed by the APC are thus readily available for presentation via MHC II molecules, and for this reason this antigen presentation pathway is usually referred to as exogenous. As membrane proteins on their way to degradation in lysosomes as part of their normal turn-over are also contained in the endosomal/lysosomal compartments, exogenous antigens must compete with those derived from endogenous components. Autophagy is also a source of endogenous peptides, autophagosomes constitutively fuse with MHC class II loading compartments. In addition to APCs, other cells of the gastrointestinal tract, such as epithelial cells, express MHC class II molecules and CD74 and act as APCs, which is an unusual trait of the GI tract. To produce a MHC class II molecule that presents an antigen, three MHC class II molecules (heterodimers of an alpha and a beta chain) associate with a CD74 trimer in the ER to form a heterononamer. Soon after the entry of this complex into the endosomal/lysosomal system where antigen processing occurs, CD74 undergoes a sequential degradation by various proteases, including CTSS and CTSL, leaving a small fragment termed CLIP (class-II-associated invariant chain peptide). The removal of CLIP is facilitated by HLA-DM via direct binding to the alpha-beta-CLIP complex so that CLIP is released. HLA-DM stabilizes MHC class II molecules until primary high affinity antigenic peptides are bound. The MHC II molecule bound to a peptide is then transported to the cell membrane surface. In B-cells, the interaction between HLA-DM and MHC class II molecules is regulated by HLA-DO. Primary dendritic cells (DCs) also to express HLA-DO. Lysosomal miroenvironment has been implicated in the regulation of antigen loading into MHC II molecules, increased acidification produces increased proteolysis and efficient peptide loading.
Subunit structure	Heterodimer of an alpha and a beta subunit; also referred as MHC class II molecule. In the endoplasmic reticulum (ER) it forms a heterononamer; 3 MHC class II molecules bind to a CD74 homotrimer (also known as invariant chain or HLA class II histocompatibility antigen gamma chain). In the endosomal/lysosomal system; CD74 undergoes sequential degradation by various proteases; leaving a small fragment termed CLIP on each MHC class II molecule. MHC class II molecule interacts with HLA_DM, and HLA_DO in B-cells, in order to release CLIP and facilitate the binding of antigenic peptides.
Subcellular location	Cell membrane; Single-pass type I membrane protein. Endoplasmic reticulum membrane; Single-pass type I membrane protein. Golgi apparatus › trans-Golgi network membrane; Single-pass type I membrane protein. Endosome membrane; Single-pass type I membrane protein. Lysosome membrane; Single-pass type I membrane protein. Late endosome membrane; Single-pass type I membrane protein. Note: The MHC class II complex transits through a number of intracellular compartments in the endocytic pathway until it reaches the cell membrane for antigen presentation. Ref.25
Post-translational modification	Ubiquitinated by MARCH1 and MARCH8 at Lys-254 leading to sorting into the endosome system and down-regulation of MHC class II Probable. Ref.25
Polymorphism	The following alleles of DRB1-12 are known: DRB1*12:01, DRB1*12:02, DRB1*12:03, DRB1*12:04, DRB1*12:05, DRB1*12:06, DRB1*12:07, DRB1*12:08, DRB1*12:09, DRB1*12:10, DRB1*12:11, DRB1*12:12, DRB1*12:13, DRB1*12:14, DRB1*12:15, DRB1*12:16, DRB1*12:17, DRB1*12:18 and DRB1*12:19. The sequence shown is that of DRB1*12:01.
Sequence similarities	Belongs to the MHC class II family. Contains 1 Ig-like C1-type (immunoglobulin-like) domain.

Ontologies

Keywords
Biological process	Immunity
Cellular component	Cell membrane Endoplasmic reticulum Endosome Golgi apparatus Lysosome MHC II Membrane
Coding sequence diversity	Polymorphism
Domain	Signal Transmembrane Transmembrane helix
PTM	Disulfide bond Glycoprotein Isopeptide bond Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	T cell costimulation Traceable author statement. Source: Reactome T cell receptor signaling pathway Traceable author statement. Source: Reactome antigen processing and presentation of exogenous peptide antigen via MHC class II Traceable author statement. Source: Reactome interferon-gamma-mediated signaling pathway Traceable author statement. Source: Reactome
Cellular_component	ER to Golgi transport vesicle membrane Traceable author statement. Source: Reactome Golgi membrane Traceable author statement. Source: Reactome MHC class II protein complex Inferred from electronic annotation. Source: UniProtKB-KW clathrin-coated endocytic vesicle membrane Traceable author statement. Source: Reactome integral to lumenal side of endoplasmic reticulum membrane Traceable author statement. Source: Reactome late endosome membrane Inferred from direct assay Ref.25. Source: UniProtKB lysosomal membrane Inferred from direct assay Ref.25. Source: UniProtKB plasma membrane Traceable author statement. Source: Reactome trans-Golgi network membrane Traceable author statement. Source: Reactome
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 29	29	Potential
	Chain	30 – 266	237	HLA class II histocompatibility antigen, DRB1-12 beta chain		PRO_0000391832
Regions
	Transmembrane	228 – 248	21	Helical; Potential
	Domain	126 – 214	89	Ig-like C1-type
Amino acid modifications
	Glycosylation	48	1	N-linked (GlcNAc...) Potential
	Disulfide bond	146 ↔ 202		By similarity
	Cross-link	254		Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity
Natural variations
	Natural variant	5	1	R → K in allele DRB1*12:17.		VAR_062818
	Natural variant	13	1	A → T in allele DRB1*12:17.		VAR_062819
	Natural variant	14	1	V → A in allele DRB1*12:17.		VAR_062820
	Natural variant	14	1	V → I in allele DRB1*12:10.		VAR_062821
	Natural variant	54	1	R → L in allele DRB1*12:13.		VAR_062822
	Natural variant	55	1	L → F in allele DRB1*12:08.		VAR_062823
	Natural variant	66	1	L → F in allele DRB1*12:05, allele DRB1*12:14 and allele DRB1*12:15.		VAR_062824
	Natural variant	67	1	L → V in allele DRB1*12:14.		VAR_062825
	Natural variant	76	1	F → L in allele DRB1*12:11.		VAR_062826
	Natural variant	86	1	V → D in allele DRB1*12:04 and allele DRB1*12:09.		VAR_062827
	Natural variant	87	1	A → E in allele DRB1*12:04.		VAR_062828
	Natural variant	88	1	E → Q in allele DRB1*12:18.		VAR_062829
	Natural variant	89	1	S → Y in allele DRB1*12:04 and allele DRB1*12:09.		VAR_062830
	Natural variant	96	1	I → F in allele DRB1*12:02, allele DRB1*12:13, allele DRB1*12:15, allele DRB1*12:16, allele DRB1*12:18 and allele DRB1*12:19.		VAR_062831
	Natural variant	96	1	I → L in allele DRB1*12:12.		VAR_062832
	Natural variant	98	1	E → G in allele DRB1*12:07.		VAR_062833
	Natural variant	114	1	A → V in allele DRB1*12:03, allele DRB1*12:16 and allele DRB1*12:19.		VAR_062834
	Natural variant	115	1	V → G in allele DRB1*12:16.		VAR_062835
	Natural variant	125	1	H → E in allele DRB1*12:17; requires 2 nucleotide substitutions.		VAR_062836
	Natural variant	169	1	T → A in allele DRB1*12:17.		VAR_062837
	Natural variant	178	1	H → Q in allele DRB1*12:06 and allele DRB1*12:17.		VAR_062838
	Natural variant	262	1	R → T in allele DRB1*12:17. Corresponds to variant rs9269744 [ dbSNP | Ensembl ].		VAR_062839

Sequences

	Sequence		Length	Mass (Da)
	Q95IE3 [UniParc]. Last modified December 1, 2001. Version 1. Checksum: FFDD0001C2F0BAF9	FASTA	266	29,878
	10 20 30 40 50 60 MVCLRLPGGS CMAVLTVTLM VLSSPLALAG DTRPRFLEYS TGECYFFNGT ERVRLLERHF 70 80 90 100 110 120 HNQEELLRFD SDVGEFRAVT ELGRPVAESW NSQKDILEDR RAAVDTYCRH NYGAVESFTV 130 140 150 160 170 180 QRRVHPKVTV YPSKTQPLQH HNLLVCSVSG FYPGSIEVRW FRNGQEEKTG VVSTGLIHNG 190 200 210 220 230 240 DWTFQTLVML ETVPRSGEVY TCQVEHPSVT SPLTVEWRAR SESAQSKMLS GVGGFVLGLL 250 260 FLGAGLFIYF RNQKGHSGLQ PRGFLS

References

[1]	"Sequence of a new DR12 allele with two silent mutations that affect PCR-SSP typing." Zanone R., Bettens F., Tiercy J.M. Tissue Antigens 59:165-167(2002) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ALLELE DRB1*12:01).
[2]	"Identification of a novel HLA-DRB1*12 allele (DRB1*1210) in the Korean population." Kim E., Lee E.J., Lim Y.H., Lee J.Y., Koh I.S., Kimm K., Ji G.E., Kwack K. Tissue Antigens 64:518-519(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ALLELE DRB1*12:10).
[3]	"Identification of a novel HLA-DRB1 allele, HLA-DRB1*1217, in a Korean individual." Park M.H., Kim Y., Lee J.Y. Tissue Antigens 73:627-628(2009) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ALLELE DRB1*12:17).
[4]	"Ancient haplotypes of the HLA Class II region." Raymond C.K., Kas A., Paddock M., Qiu R., Zhou Y., Subramanian S., Chang J., Palmieri A., Haugen E., Kaul R., Olson M.V. Genome Res. 15:1250-1257(2005) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-262 (ALLELE DRB1*12:01).
[5]	"Description of a novel HLA-DRB1 allele, DRB1*1207." Dunckley H., Le T., Dodd R., Hogbin J.P., Strickland J., Chapman G., Greville W.D. Tissue Antigens 59:162-164(2002) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 35-208 (ALLELE DRB1*12:07).
[6]	"The replacement mutation in HLA-DRB1*1211 affects a likely keystone position." Horn P.A., DeLuca D.S., Jindra P., Blasczyk R. Hum. Immunol. 66:1254-1257(2005) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 35-123 (ALLELE DRB1*12:11). Tissue: Peripheral blood.
[7]	"Identification of two new alleles in a single Korean individual, HLA-B*1568 and HLA-DRB1*1208." Sheldon M.H., Bunce M., Dunn P.P., Day S., Lee G.D., Park Y.J., Bang B.K., Kim B.K., Oh E.J. Tissue Antigens 59:430-432(2002) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 35-123 (ALLELE DRB1*12:08).
[8]	"Identification of two novel HLA-DRB1 alleles, HLA-DRB1*1214 and HLA-DRB1*1215, in two Taiwanese individuals." Lee H.L., Chu C.C., Trejaut J.A., Yang K.L., Lin M. Int. J. Immunogenet. 35:423-426(2008) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 35-123 (ALLELE DRB1*12:15).
[9]	"A novel HLA-DRB1 allele, DRB1*1219, was identified by sequence-based typing in a Chinese leukaemia family." Nie X.M., Fang Y.H., Zhang Y., He W.D., Zhu C.F. Tissue Antigens 74:352-354(2009) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 35-123 (ALLELE DRB1*12:19).
[10]	"Identification of a novel HLA-DRB1*12 allele, DRB1*1218, in Chinese population." Gao S.Q., Deng Z.H., Xu Y.P. Tissue Antigens 74:265-267(2009) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 35-123 (ALLELE DRB1*12:18).
[11]	"Sequence of new allele." Kashiwase K., Tokunaga K., Akaza T., Tadokoro K., Juji T. Submitted (JUL-1996) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 35-123 (ALLELE DRB1*12:05).
[12]	"A new HLA-DR12V allele detected by PCR-RFLP." Ono A. Submitted (JUN-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 35-123 (ALLELE DRB1*12:09).
[13]	Gedil M.A., Steiner N.K., Hurley C.K. Submitted (JUL-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 35-123 (ALLELE DRB1*12:04).
[14]	"Identification a novel HLA-DRB1*12 in Chinese by sequence-based typed." Zhu F., Lu Q., Zhang W. Submitted (JAN-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 35-123 (ALLELE DRB1*12:12).
[15]	"Novel HLA-DRB1*120201 variant allele." Hur S.S., Lee M.N., Park S.Y., Kwon O.J. Submitted (OCT-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 35-123 (ALLELE DRB1*12:13).
[16]	"A novel HLA-DRB1 allele." Chu C.-C. Submitted (DEC-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 35-123 (ALLELE DRB1*12:14).
[17]	Zhang C., Liu J. Submitted (JUN-2007) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 35-123 (ALLELE DRB1*12:16).
[18]	"Sequence analysis of three novel HLA-DRB1 alleles: DRB1*1113, DRB1*1114 and DRB1*12032." Hashemi S., Couture C., Buyse I., Cole R., Aye M.T. Tissue Antigens 47:155-158(1996) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 35-122 (ALLELE DRB1*12:03).
[19]	"HLA class II DRB1*120201 confirmatory sequence." Lo B. Submitted (NOV-2002) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 36-123 (ALLELE DRB1*12:02).
[20]	"A novel HLA-DR12 allele (DRB1*1206) found in a Korean B-cell line." Maeng C.Y., Kim K.H., Kang J.H., Han H., Kim K.L. Tissue Antigens 53:516-518(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 88-197 (ALLELE DRB1*12:06).
[21]	"Invariant chain structure and MHC class II function." Cresswell P. Cell 84:505-507(1996) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW.
[22]	"Presentation of antigens by MHC class II molecules: getting the most out of them." Villadangos J.A. Mol. Immunol. 38:329-346(2001) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW.
[23]	"Autophagy in MHC class II presentation: sampling from within." Menendez-Benito V., Neefjes J. Immunity 26:1-3(2007) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW.
[24]	"MHC class II molecules on the move for successful antigen presentation." Rocha N., Neefjes J. EMBO J. 27:1-5(2008) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW.
[25]	"MHC class II stabilization at the surface of human dendritic cells is the result of maturation-dependent MARCH I down-regulation." De Gassart A., Camosseto V., Thibodeau J., Ceppi M., Catalan N., Pierre P., Gatti E. Proc. Natl. Acad. Sci. U.S.A. 105:3491-3496(2008) [PubMed] [Europe PMC] [Abstract] Cited for: UBIQUITINATION BY MARCH1, SUBCELLULAR LOCATION.
[26]	"MHC class II transport at a glance." Berger A.C., Roche P.A. J. Cell Sci. 122:1-4(2009) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW.
[27]	"CD74 in antigen presentation, inflammation, and cancers of the gastrointestinal tract." Beswick E.J., Reyes V.E. World J. Gastroenterol. 15:2855-2861(2009) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AJ302075 mRNA. Translation: CAC44379.1. AY626551 mRNA. Translation: AAV34808.1. EU375850 mRNA. Translation: ABY78039.1. AY663396 Genomic DNA. Translation: AAU87983.1. AH010330 Genomic DNA. Translation: AAK07563.1. AJ870921 Genomic DNA. Translation: CAI35044.1. AY033428 Genomic DNA. Translation: AAK55114.1. DQ533486 Genomic DNA. Translation: ABF74752.1. FJ374889 Genomic DNA. Translation: ACJ09136.1. FJ481086 Genomic DNA. Translation: ACK77491.1. D86503 Genomic DNA. Translation: BAA13098.1. AB112911 Genomic DNA. Translation: BAD02942.1. AY339246 Genomic DNA. Translation: AAQ18913.1. AY899825 Genomic DNA. Translation: AAW82078.1. DQ250650 Genomic DNA. Translation: ABC59072.1. DQ343834 Genomic DNA. Translation: ABC70992.1. EF688603 Genomic DNA. Translation: ABS11697.1. X83455 Genomic DNA. No translation available. AY174091 Genomic DNA. Translation: AAO20088.1. AF017439 mRNA. Translation: AAB70553.1.
IPI	IPI00955461.
PIR	C60748. F60748. PH0154.
UniGene	Hs.534322. Hs.696211. Hs.716081. Hs.723344. Hs.736560.
3D structure databases
HSSP	HSSP built from PDB template 1JWU based on UniProtKB P01903.
ProteinModelPortal	Q95IE3.
SMR	Q95IE3. Positions 34-220.
ModBase	Search...
Polymorphism databases
DMDM	74760669.
Proteomic databases
PRIDE	Q95IE3.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000328980; ENSP00000331343; ENSG00000206306. ENST00000399450; ENSP00000382378; ENSG00000206240. ENST00000412634; ENSP00000408795; ENSG00000228080. ENST00000415796; ENSP00000412168; ENSG00000206306. ENST00000419393; ENSP00000403458; ENSG00000228080. ENST00000428566; ENSP00000392280; ENSG00000206240.
Organism-specific databases
GeneCards	GC06M032546. GC06Mn32480.
HGNC	HGNC:4948. HLA-DRB1.
neXtProt	NX_Q95IE3.
GenAtlas	Search...
Phylogenomic databases
HOVERGEN	HBG012730.
Enzyme and pathway databases
Reactome	REACT_6900. Immune System.
Gene expression databases
ArrayExpress	Q95IE3.
Family and domain databases
Gene3D	2.60.40.10. 1 hit. 3.10.320.10. 1 hit.
InterPro	IPR007110. Ig-like_dom. IPR013783. Ig-like_fold. IPR003006. Ig/MHC_CS. IPR003597. Ig_C1-set. IPR011162. MHC_I/II-like_Ag-recog. IPR014745. MHC_II_a/b_N. IPR000353. MHC_II_b_N. [Graphical view]
Pfam	PF07654. C1-set. 1 hit. PF00969. MHC_II_beta. 1 hit. [Graphical view]
ProDom	PD000328. MHC_II_b_N. 1 hit. [Graphical view] [Entries sharing at least one domain]
SMART	SM00407. IGc1. 1 hit. SM00921. MHC_II_beta. 1 hit. [Graphical view]
SUPFAM	SSF54452. MHC_I/II-like_Ag-recog. 1 hit.
PROSITE	PS50835. IG_LIKE. 1 hit. PS00290. IG_MHC. 1 hit. [Graphical view]
ProtoNet	Search...
Other
ChiTaRS	HLA-DRB1. human.

Entry information

Entry name

2B1C_HUMAN

Accession

Primary (citable) accession number: Q95IE3
Secondary accession number(s): A7LA26 , B0LUZ6, B6VCX2, B7UDB2, O19585, Q19AF2, Q29771, Q2L9H4, Q2MZ92, Q5EER6, Q5NDB9, Q5UT58, Q5Y7G0, Q768U4, Q7YP04, Q861H8, Q95IT6, Q9BD40

Entry history

Integrated into UniProtKB/Swiss-Prot:	March 2, 2010
Last sequence update:	December 1, 2001
Last modified:	April 3, 2013
This is version 87 of the entry and version 1 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.