PubMed · 8640213
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T Elliott. 1996. Tapping into tumours.. https://doi.org/10.1038/ng0696-139
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Polymerase chain reaction amplification of cDNA from rat intestine revealed the expression of a novel ABC transporter, TAPL (TAP-like). Subsequently, the protein sequence was deduced from the nucleotide sequence of cDNA carrying the entire coding region. TAPL is transcribed ubiquitously in various rat tissues. The protein, with 762 amino acid residues, has potential transmembrane domains, and an ATP-binding domain in its amino and carboxyl terminal regions, respectively, and is highly homologous to TAP1 and TAP2 (transporters associated with antigen presentation/processing): pairwise comparisons with TAPL demonstrated 39 and 41% of the residues are identical, respectively. These numerical values are essentially the same as that for TAP1 and TAP2 (39%), and the hydropathy profiles of TAPL, TAP1 and TAP2 are quite similar. The similarity among these three proteins suggests that they could be derived from a common ancestral gene. Furthermore, we found that there is a potential splicing isoform, sharing the amino terminal 720 amino acid residues of TAPL.
Transient interactions between molecular chaperones and nascent polypeptide chains assist protein folding in the endoplasmic reticulum. In an experimental setting that resembles the ER, we have used peptides as model substrates to identify and compare substrate specificities of ER-resident chaperones. The ER-located peptide transporter TAP was used to introduce peptides into the lumen of microsomes. In addition to PDI and gp96, previously identified as peptide-binding chaperones in the ER, we show that ERp72, calnexin, and grp170 interact with TAP-translocated peptides. The chaperones that have been identified can all bind peptide substrates that range from 8 to 40 amino acids in a manner independent of ATP. In addition, these chaperones exhibit broad and largely overlapping, however not identical, substrate selectivities. Our data indicate that peptide translocation into microsomes via TAP can be used as a method to monitor substrate selectivities of ER-resident chaperones. The implications of the observed preferences for chaperone-substrate interactions and for chaperones applied as vehicles in peptide-based vaccination strategies will be discussed.
We used a new monoclonal antibody (mAb 130) to analyze the intracellular trafficking and surface expression of H2-M3, the major histocompatibility complex class Ib molecule that presents N-formylated peptides to cytotoxic T cells. M3 surface expression is undetectable in most cell types due to the paucity of endogenous antigen. M3 is induced on the cell surface by addition of high-affinity N-formylated peptides from mitochondria and listeria. Peptide-induced M3 expression is most efficient on antigen presenting cells. Basal and inducible expression of M3 is transporter associated with antigen processing (TAP)-dependent, distinguishing M3 from the class Ib molecules TL and CD1. Unlike the expression of class Ia molecules and a previously described M3/L(d) chimera, surface expression of M3 cannot be rescued by lowered temperature, suggesting that the alpha3 domain and transmembrane region of M3 may control trafficking. Pulse-chase analysis and use of trafficking inhibitors revealed a pool of empty M3 in the endoplasmic reticulum or early Golgi apparatus. Addition of exogenous peptide allows maturation with kinetics matching those of D(d). The lack of endogenous N-formylated peptide allows discovery of novel pathogen-derived peptides in normal antigen presenting cells. The nonpolymorphic nature of M3 and its ability to present bacterial antigens rapidly and dominantly make it an attractive target for peptide vaccination strategies.