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3.A.1.209.1
MHC heterodimeric peptide exporter (TAP) (from cytoplasm to the endoplasmic reticulum) (TAP1=ABCB2; TAP2=ABCB3) (defects in TAP1 or TAP2 cause immunodeficiency) (TAP1/TAP2 is stabilized by tapasin isoforms 1, 2 and 3) (Raghuraman et al., 2002). TAP1 has 10 TMSs, 4 unique N-terminal TMSs and 6 TMSs that form the translocation pore with N- and C-termini in the cytosol (Schrodt et al., 2006). The TAP2 nucleotide binding site appears to be the main catalytic active site driving transport suggesting asymmetry in the transporter (Perria et al., 2006). The TAP complex shows strict coupling between peptide binding and ATP hydrolysis, revealing no basal ATPase activity in the absence of peptides (Herget et al., 2009).  There are three binding sites on TAP1 for tapasis which interconnects TAP and MHC class I, promotes TAP stability and facilitates heterodimerization (Leonhardt et al. 2014).  TAP is the target of GN1 (TC#8.B.25.1.1), a virally encoded protein inhibitor of viral peptide exposure on the cell surface (Verweij et al. 2008; Rufer et al. 2015). Tapasin (448 aas; O15533) stabilizes TAP2 (Papadopoulos and Momburg 2007). Tapasin is involved in the association of MHC class I with the transporter associated with antigen processing (TAP) and in the assembly of MHC class I with peptide (peptide loading). TAP plays a key role in the adaptive immune defense against infected or malignantly transformed cells by translocating proteasomal degradation products into the lumen of the endoplasmic reticulum for loading onto MHC class I molecules. TAP transports peptides from 8 to 40 residues, including even branched or modified molecules, suggestive of structural flexibility of the substrate-binding pocket. The bound peptides in side-chains' mobility was strongly restricted at the ends of the peptide, whereas the central region was flexible. Peptides bind to TAP in an extended kinked structure, analogous to those bound to MHC class I proteins (Herget et al., 2011). TAP translocates proteasomal degradation products from the cytosol into the lumen of the endoplasmic reticulum, where these peptides are loaded onto MHC class I molecules by a macromolecular peptide-loading complex (PLC) and subsequently shuttled to the cell surface for inspection by cytotoxic T lymphocytes. As a central adapter protein, tapasin (O15533) (Li et al. 2000) recruits other components of the PLC at the N-terminal domains of TAP. Koch et al. 2006 found that the N-terminal domains of human TAP1 and TAP2 independently bind to tapasin, thus providing two separate loading platforms for PLC assembly. Tapasin binding is dependent on the first N-terminal TMS of TAP1 and TAP2, demonstrating that these two helices contribute independently to the recruitment of tapasin and associated factors (Koch et al. 2006). The endoplasmic reticulum-resident human cytomegalovirus glycoprotein US6 (gpUS6) inhibits peptide translocation by the transporter associated with antigen processing (TAP) to prevent loading of major histocompatibility complex class I molecules and antigen presentation to CD8+ T cells. gpUS6 associates with preformed TAP1/2 heterodimers (Halenius et al. 2006).

Accession Number:Q03518
Protein Name:TAP1 aka ABCB2 aka PSF1 aka RING4 aka Y3
Length:808
Molecular Weight:87218.00
Species:Homo sapiens (Human) [9606]
Number of TMSs:8
Location1 / Topology2 / Orientation3: Endoplasmic reticulum membrane1 / Multi-pass membrane protein2
Substrate peptides

Cross database links:

Genevestigator: Q03518
eggNOG: prNOG04363
HEGENOM: HBG758042
RefSeq: NP_000584.2   
Entrez Gene ID: 6890   
Pfam: PF00664    PF00005   
Drugbank: Drugbank Link   
OMIM: 170260  gene
604571  phenotype
KEGG: hsa:6890   

Gene Ontology

GO:0005829 C:cytosol
GO:0030176 C:integral to endoplasmic reticulum membrane
GO:0042825 C:TAP complex
GO:0043531 F:ADP binding
GO:0005524 F:ATP binding
GO:0042626 F:ATPase activity, coupled to transmembrane m...
GO:0042605 F:peptide antigen binding
GO:0015197 F:peptide transporter activity
GO:0042803 F:protein homodimerization activity
GO:0046978 F:TAP1 binding
GO:0046979 F:TAP2 binding
GO:0019885 P:antigen processing and presentation of endo...
GO:0046967 P:cytosol to ER transport
GO:0006955 P:immune response
GO:0019060 P:intracellular transport of viral proteins i...
GO:0015833 P:peptide transport
GO:0055085 P:transmembrane transport

References (23)

[1] “Sequences encoded in the class II region of the MHC related to the 'ABC' superfamily of transporters.”  Trowsdale J.et.al.   2259383
[2] “DNA sequence analysis of 66 kb of the human MHC class II region encoding a cluster of genes for antigen processing.”  Beck S.et.al.   1453454
[3] “Evolutionary dynamics of non-coding sequences within the class II region of the human MHC.”  Beck S.et.al.   8568858
[4] “The DNA sequence and analysis of human chromosome 6.”  Mungall A.J.et.al.   14574404
[5] “The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).”  The MGC Project Teamet.al.   15489334
[6] “TAP1 alleles in insulin-dependent diabetes mellitus: a newly defined centromeric boundary of disease susceptibility.”  Jackson D.G.et.al.   8248212
[7] “A gene in the human major histocompatibility complex class II region controlling the class I antigen presentation pathway.”  Spies T.et.al.   2259384
[8] “New allelic polymorphisms in TAP genes.”  Szafer F.et.al.   8168860
[9] “Two putative subunits of a peptide pump encoded in the human major histocompatibility complex class II region.”  Bahram S.et.al.   1946428
[10] “Molecular mechanism and species specificity of TAP inhibition by herpes simplex virus ICP47.”  Ahn K.et.al.   8670825
[11] “Multiple regions of the transporter associated with antigen processing (TAP) contribute to its peptide binding site.”  Nijenhuis M.et.al.   8955196
[12] “Downregulation of TAP1 in B lymphocytes by cellular and Epstein-Barr virus-encoded interleukin-10.”  Zeidler R.et.al.   9310490
[13] “The ER-luminal domain of the HCMV glycoprotein US6 inhibits peptide translocation by TAP.”  Ahn K.et.al.   9175839
[14] “Splice acceptor site mutation of the transporter associated with antigen processing-1 gene in human bare lymphocyte syndrome.”  Furukawa H.et.al.   10074494
[15] “Adenovirus E19 has two mechanisms for affecting class I MHC expression.”  Bennett E.M.et.al.   10227971
[16] “The human cytomegalovirus gene product US6 inhibits ATP binding by TAP.”  Hewitt E.W.et.al.   11157746
[17] “Cytoplasmic domains of the transporter associated with antigen processing and P-glycoprotein interact with subunits of the proteasome.”  Begley G.S.et.al.   15488952
[18] “Specific targeting of the EBV lytic phase protein BNLF2a to the transporter associated with antigen processing results in impairment of HLA class I-restricted antigen presentation.”  Horst D.et.al.   19201886
[19] “Structure of the ABC ATPase domain of human TAP1, the transporter associated with antigen processing.”  Gaudet R.et.al.   11532960
[20] “Allelic variants of the human putative peptide transporter involved in antigen processing.”  Colonna M.et.al.   1570316
[21] “A functionally defective allele of TAP1 results in loss of MHC class I antigen presentation in a human lung cancer.”  Chen H.L.et.al.   8640228
[22] “TAP1 polymorphisms in several human ethnic groups: characteristics, evolution, and genotyping strategies.”  Tang J.et.al.   11250043
[23] “Novel TAP1 polymorphisms in indigenous Zimbabweans: their potential implications on TAP function and in human diseases.”  Lajoie J.et.al.   12878362
Structure:
1JJ7     

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FASTA formatted sequence
1:	MAELLASAGS ACSWDFPRAP PSFPPPAASR GGLGGTRSFR PHRGAESPRP GRDRDGVRVP 
61:	MASSRCPAPR GCRCLPGASL AWLGTVLLLL ADWVLLRTAL PRIFSLLVPT ALPLLRVWAV 
121:	GLSRWAVLWL GACGVLRATV GSKSENAGAQ GWLAALKPLA AALGLALPGL ALFRELISWG 
181:	APGSADSTRL LHWGSHPTAF VVSYAAALPA AALWHKLGSL WVPGGQGGSG NPVRRLLGCL 
241:	GSETRRLSLF LVLVVLSSLG EMAIPFFTGR LTDWILQDGS ADTFTRNLTL MSILTIASAV 
301:	LEFVGDGIYN NTMGHVHSHL QGEVFGAVLR QETEFFQQNQ TGNIMSRVTE DTSTLSDSLS 
361:	ENLSLFLWYL VRGLCLLGIM LWGSVSLTMV TLITLPLLFL LPKKVGKWYQ LLEVQVRESL 
421:	AKSSQVAIEA LSAMPTVRSF ANEEGEAQKF REKLQEIKTL NQKEAVAYAV NSWTTSISGM 
481:	LLKVGILYIG GQLVTSGAVS SGNLVTFVLY QMQFTQAVEV LLSIYPRVQK AVGSSEKIFE 
541:	YLDRTPRCPP SGLLTPLHLE GLVQFQDVSF AYPNRPDVLV LQGLTFTLRP GEVTALVGPN 
601:	GSGKSTVAAL LQNLYQPTGG QLLLDGKPLP QYEHRYLHRQ VAAVGQEPQV FGRSLQENIA 
661:	YGLTQKPTME EITAAAVKSG AHSFISGLPQ GYDTEVDEAG SQLSGGQRQA VALARALIRK 
721:	PCVLILDDAT SALDANSQLQ VEQLLYESPE RYSRSVLLIT QHLSLVEQAD HILFLEGGAI 
781:	REGGTHQQLM EKKGCYWAMV QAPADAPE