Transporter associated with antigen processing

Transporter associated with antigen processing (TAP) protein complex belongs to the ATP-binding-cassette transporter family.[1] It delivers cytosolic peptides into the endoplasmic reticulum (ER), where they bind to nascent MHC class I molecules.[2]

transporter 1, ATP-binding cassette, sub-family B (MDR/TAP)
Identifiers
SymbolTAP1
Alt. symbolsABCB2
NCBI gene6890
HGNC43
OMIM170260
RefSeqNM_000593
UniProtQ03518
Other data
LocusChr. 6 p21.3
transporter 2, ATP-binding cassette, sub-family B (MDR/TAP)
Identifiers
SymbolTAP2
Alt. symbolsABCB3
NCBI gene6891
HGNC44
OMIM170261
RefSeqNM_000544
UniProtQ03519
Other data
LocusChr. 6 p21.3

The TAP structure is formed of two proteins: TAP-1 and TAP-2, which have one hydrophobic region and one ATP-binding region each. They assemble into a heterodimer, which results in a four-domain transporter.[3]

Function

The TAP transporter is found in the ER lumen associated with the peptide-loading complex (PLC). This complex of β2 microglobulin, calreticulin, ERp57, TAP, tapasin, and MHC class I acts to keep hold of MHC molecules until they have been fully loaded with peptides.[4]

Peptide transport

TAP-mediated peptide transport is a multistep process. The peptide-binding pocket is formed by TAP-1 and TAP-2. Association with TAP is an ATP-independent event, ‘in a fast bimolecular association step, peptide binds to TAP, followed by a slow isomerisation of the TAP complex’.[5] It is suggested that the conformational change in structure triggers ATP hydrolysis and so initiates peptide transport.[6]

Both nucleotide-binding domains (NBDs) are required for peptide translocation, as each NBD cannot hydrolyse ATP alone. The exact mechanism of transport is not known; however, findings indicate that ATP binding to TAP-1 is the initial step in the transport process, and that ATP bound to TAP-1 induces ATP binding in TAP-2. It has also been shown that undocking of the loaded MHC class I is linked to the transport cycle of TAP caused by signals from the TAP-1 subunit.[7]

Transport of mRNA out of the nucleus

Yeast protein Mex67p and human NXF1, also-called TAP, are the two best-characterized NXFs (nuclear transport factors). TAPs mediate the interaction of the messenger ribonucleoprotein particle (mRNP) and the nuclear pore complex (NPC).NXFs bear no resemblance to prototypical nuclear transport receptors of the importin – exportin (karyopherin) family and lack the characteristic Ran-binding domain found in all karyopherins.

Specificity

The ATPase activity of TAP is highly dependent on the presence of the correct substrate, and peptide binding is prerequisite for ATP hydrolysis. This prevents waste of ATP via peptide-independent hydrolysis.[6]

The specificity of TAP proteins was first investigated by trapping peptides in the ER using glycosylation. TAP binds to 8- to 16-residue peptides with equal affinity, while translocation is most efficient for peptides that are 8 to 12 residues long. Efficiency reduces for peptides longer than 12 residues.[8] However, peptides with more than 40 residues were translocated, albeit with low efficiency. Peptides with low affinity for the MHC class I molecule are transported out of the ER by an efficient ATP-dependent export protein. These outlined mechanisms may represent a mechanism for ensuring that only high-affinity peptides are bound to MHC class I.[9]

See also

References
  1. Daumke O, Knittler MR (2001). "Functional asymmetry of the ATP-binding-cassettes of the ABC transporter TAP is determined by intrinsic properties of the nucleotide binding domains". Eur. J. Biochem. 268 (17): 4776–86. doi:10.1046/j.1432-1327.2001.02406.x. PMID 11532014.
  2. Suh WK, Cohen-Doyle MF, Fruh K, Wang K, Peterson PA, Williams DB (1994). "Interaction of MHC class I molecules with the transporter associated with antigen processing". Science. 264 (5163): 1322–6. doi:10.1126/science.8191286. PMID 8191286.
  3. Janeway CA, Travers P, Walport M, Shlomchik M (2001). "Chapter 5, Antigen Presentation to T-lymphocytes". In Janeway, Charles (ed.). Immunobiology: the immune system in health and disease (5th ed.). New York: Garland. ISBN 0-8153-3642-X.
  4. Antoniou AN, Powis SJ, Elliott T (2003). "Assembly and export of MHC class I peptide ligands". Curr. Opin. Immunol. 15 (1): 75–81. doi:10.1016/S0952-7915(02)00010-9. PMID 12495737.
  5. van Endert PM, Tampé R, Meyer TH, Tisch R, Bach JF, McDevitt HO (1994). "A sequential model for peptide binding and transport by the transporters associated with antigen processing". Immunity. 1 (6): 491–500. doi:10.1016/1074-7613(94)90091-4. PMID 7895159.
  6. Neumann L, Tampé R (1999). "Kinetic analysis of peptide binding to the TAP transport complex: evidence for structural rearrangements induced by substrate binding". J. Mol. Biol. 294 (5): 1203–13. doi:10.1006/jmbi.1999.3329. PMID 10600378. S2CID 38730297.
  7. Alberts P, Daumke O, Deverson EV, Howard JC, Knittler MR (2001). "Distinct functional properties of the TAP subunits coordinate the nucleotide-dependent transport cycle". Curr. Biol. 11 (4): 242–51. doi:10.1016/S0960-9822(01)00073-2. PMID 11250152. S2CID 16476417.
  8. Neefjes JJ, Momburg F, Hämmerling GJ (1993). "Selective and ATP-dependent translocation of peptides by the MHC-encoded transporter". Science. 261 (5122): 769–71. doi:10.1126/science.8342042. PMID 8342042.
  9. Lankat-Buttgereit B, Tampé R (2002). "The transporter associated with antigen processing: function and implications in human diseases". Physiol. Rev. 82 (1): 187–204. doi:10.1152/physrev.00025.2001. PMID 11773612. S2CID 12508247.
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