Content uploaded by Franz Tumulka
Author content
All content in this area was uploaded by Franz Tumulka on Apr 09, 2014
Content may be subject to copyright.
Biol. Chem., Vol. 392, pp. 61–66, January/February 2011 •Copyright by Walter de Gruyter •Berlin •New York. DOI 10.1515/BC.2011.007
2011/267
Article in press - uncorrected proof
Minireview
The lysosomal polypeptide transporter TAPL: more than
a housekeeping factor?
Irina Bangert, Franz Tumulka and Rupert Abele*
Institute of Biochemistry, Biocenter, Goethe University
Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt/Main,
Germany
* Corresponding author
e-mail: abele@em.uni-frankfurt.de
Abstract
The transporter associated with antigen processing-like
(TAPL) is a polypeptide transporter translocating cytosolic
peptides into the lumen of lysosomes driven by ATP hydrol-
ysis. TAPL belongs to the family of ABC transporters and
forms a homodimer. This ABC transporter not only shows a
broad tissue but also a wide phylogenetic distribution,
because orthologs are still found in nematodes and insects.
Here, we present the topology, substrate specificity, and dis-
tribution of this intracellular polypeptide transporter. Addi-
tionally, we will discuss its proposed physiological functions
such as housekeeping together with a specialized factor for
metabolite storage as well as for the adaptive immunity.
Keywords: antigen processing; lysosomes; peptide
specificity; peptide transport; subcellular targeting;
truncation.
Introduction: TAPL and the ABC transporter
family
The ATP binding cassette (ABC) transporters comprise a
family of membrane proteins, which use the energy of ATP
hydrolysis for solute transport across membranes (Higgins,
1992). This family is found in bacteria, archaea, and eukary-
otes. The ABC transporter family belongs to the primary
active transporters and forms one of the largest classes of
transport proteins. The substrate specificity ranges from sug-
ars and amino acids, hydrophilic drugs, and lipids to large
proteins (Schmitt and Tampe´, 2002). ABC transporters are
involved in different cellular functions such as nutrient
uptake, iron and cholesterol homeostasis, potassium conduc-
tance, adaptive immunity, etc. (Borst and Elferink, 2002).
Malfunction of single ABC transporters is connected with
diseases such as adenoleukodystrophy, diabetes mellitus, cys-
tic fibrosis, and bare lymphocyte syndrome. Moreover,
strong expression of P-glycoprotein in tumor cells leads to
multidrug resistance interfering with chemotherapy. ABC
transporters are localized at the plasma membrane but are
also found in the membrane of various organelles. In animals
they function exclusively as exporters, whereas in prokary-
otes there are ABC exporters and ABC importers. Common
to all ABC transporters is their modular architecture com-
posed of two transmembrane domains (TMDs) and two
nucleotide binding domains (NDBs) (Schmitt and Tampe´,
2000). In general, the TMD of ABC exporters comprises
2=6 transmembrane spanning helices which form the solute
binding site and the translocation pathway. The cytosolic
nucleotide binding domains contain conserved motifs such
as Walker A and B, C-loop (ABC signature motif), and D-
loop which are involved in binding and hydrolyzing ATP for
energizing solute transport. In eukaryotes, ABC transporters
are encoded as full transporters consisting of one polypeptide
with two TMDs and two NBDs, or as half-transporters com-
posed of one TMD and one NBD. Therefore, half-transport-
ers can form homo- or heterodimers (Jones and George,
2004).
In the human, 49 ABC proteins are identified and classi-
fied in seven subfamilies (ABCA–ABCG), whereas mem-
bers of ABCE and ABCF subfamilies are soluble proteins
involved in DNA repair and translation (Dean et al., 2001).
The transporter associated with antigen processing-like
(TAPL, ABCB9) belongs to the subfamily B which contains
11 ABC transporters such as the multidrug resistance pro-
teins MDR1 and MDR3, and the transporter associated with
antigen processing TAP. TAPL, TAP, and ABCB10, the hom-
olog of yeast MDL1p, resemble intracellular polypeptide
transporters. MDL1p resides in the inner membrane of mito-
chondria and exports degradation products of mitochondrial
proteins out of the matrix (Young et al., 2001). The hetero-
dimeric TAP complex composed of the half-transporters
TAP1 and TAP2 pumps antigenic peptides from the cytosol
into the lumen of the endoplasmic reticulum for loading onto
major histocompatibility complex (MHC) class I molecules
(Abele and Tampe´, 2009). The half-transporter TAPL trans-
locates as homodimer peptides from the cytosol into the
lumen of lysosomes. TAPL forms together with TAP1 and
TAP2 the TAP subfamily. TAPL shows a sequence identity
of 38% and 40% to TAP1 and TAP2, respectively. Based on
sequence alignments and hydrophobicity analysis, the N-ter-
minal TMD is composed of 10 transmembrane helices (Fig-
ure 1). Interestingly, the TMD can be subdivided into a core
TMD with six C-terminal transmembrane helices, which
62 I. Bangert et al.
Article in press - uncorrected proof
Figure 1 Topology of TAPL.
Each subunit of homodimeric TAPL (light and dark gray) comprises an N-terminal TMD and a C-terminal NBD. Based on sequence
alignments and functional studies, TAPL can be divided into the core complex, comprising the six C-terminal transmembrane helices
(TMHs) and the NBDs, and the four TMHs containing TMD0. In homology to TAP, the peptide binding site is presumably composed of
the cytosolic loop between TMH4 and TMH5, and a short stretch after TMH6 of the core complex (dashed line). The NBDs bind and
hydrolyze ATP which drives peptide transport. The NBDs were modeled on the structure of the TAP1 NBD dimer (2IXE). ATP sandwiched
between both NBDs is depicted by spheres.
shows a high sequence identity to TAP1 and TAP2, and the
N-terminal four transmembrane helices containing domain
(TMD0) presenting no sequence identity to any protein in
the databases.
Gene organization
The human tapl gene is localized on chromosome 12q24
(Allikmets et al., 1996; Kobayashi et al., 2000). The pro-
moter region does not contain any canonical TATA-box or
CCAAT-box. However, as common for TATA-less promot-
ers, this region is GC-rich. These GC-boxes resemble mul-
tiple binding sites for the ubiquitous transcription factor Sp1
explaining the expression of TAPL in various tissues. Addi-
tionally, an NF-kB site is present. The promoter region con-
tains consensus sequences for brain-specific (Brn-2 and
HNF3b) (Li et al., 1993; Overdier et al., 1994) and testis-
specific (SRY, Sox-5, and FoxD1) (Denny et al., 1992; Pon-
tiggia et al., 1994; Dahle et al., 2002) expression. In contrast
to tap1 and tap2 genes, tapl lacks interferon-gand STAT
binding sites. Therefore, tapl is not inducible by the adaptive
immunity activating cytokine interferon-g. Interestingly,
exon organization of tapl and tap2 are very similar. Both
genes possess a non-coding first exon followed by 11 coding
exons with identical length. However, the introns of the tapl
gene are significantly longer than that of the tap2 gene
(Kobayashi et al., 2003; Uinuk-ool et al., 2003). For human
TAPL, four different splice variants are reported. Three
splice variants show differences in exon 12. Splice variant
12A encodes for the full-length TAPL with 766 amino acids
and comprises all conserved motifs in the NBD. In contrast,
the splice isoforms 12B (683 amino acids) and 12C (681
amino acids) are much shorter at the C-terminal end and lack
the highly conserved H-loop which is important for ATP
hydrolysis. Whether these shorter isoforms are still active in
transport or have regulatory function is not yet solved. The
fourth splice variant is missing exon 7 which encodes for a
43 amino acid long stretch covering a part of the last C-
terminal cytosolic loop and transmembrane helix 9 of the
TMD (Zhang et al., 2000; Kobayashi et al., 2003). In rat
four C-terminal splice isoforms were detected, whereas two
of them are again deficient of the essential H-loop (Yama-
guchi et al., 2004).
Phylogenetic relationship
Orthologs of TAPL, but not of TAP, are not only found in
higher vertebrates but also in lower vertebrates such as sea
lamprey and even in invertebrates such as Caenorhabditis
elegans. Because the sequence identity among human or
rodent TAPL, TAP1, and TAP2 is approximately 40%, it can
be assumed that these three genes split at the same time.
However, the evolutionary rate of tapl is drastically
decreased in comparison to the tap genes. Thus, the primary
sequence of rat and mouse are 99% identical and 95% iden-
tity can be found between human and rodent in a pairwise
comparison. In contrast, only 75% of residues are identical
between TAP1 and TAP2 of rodent and human and 90%
between mouse and rat (Kobayashi et al., 2000). In conclu-
sion, it can be speculated that TAPL is the ancestor of the
The lysosomal polypeptide transporter TAPL 63
Article in press - uncorrected proof
TAP family with more general function than in the cellular
immunity found only in higher vertebrates.
Expression pattern and subcellular localization
Originally, ubiquitous expression of TAPL in various rat tis-
sues was observed by RT-PCR (Yamaguchi et al., 1999).
However, strong expression of TAPL was reported in testes,
spinal cord, and brain by Northern blot analysis (Zhang et
al., 2000). On the cellular level, TAPL expression was
detected in transformed cells such as HEK293 and HeLa and
also in non-transformed cells such as lymphocytes and Ser-
toli cells (Zhang et al., 2000; Kobayashi et al., 2003).
Remarkably, TAPL expression is strongly upregulated during
the maturation of monocytes to dendritic cells and macro-
phages. Although TAPL is strongly expressed in professional
antigen presenting cells, it is not involved in the classical
MHC class I antigen presentation pathway, because it does
not restore MHC class I surface expression in TAP1- or
TAP2-deficient cells (Demirel et al., 2007). Moreover, it does
not form heterodimeric complexes with any of the TAP subu-
nits (Leveson-Gower et al., 2004).
Although there were some controversial reports in the
beginning, it became evident that the subcellular localization
of TAPL is restricted to lysosomes, shown by immunofluo-
rescence microscopy as well as subcellular fractionation of
TAPL overexpressed in different cell lines (Zhang et al.,
2000; Demirel et al., 2007, 2010). Because overexpression
can induce mistargeting of proteins, the lysosomal localiza-
tion was proven with endogenous levels of TAPL in the
monocytic cell line THP-1 upon stimulation with Escheri-
chia coli or lipopolysaccharide inducing the differentiation
to macrophage-like cells (Demirel et al., 2007).
Substrate specificity
The function of TAPL as an ATP-dependent peptide pump
was first demonstrated with crude membranes derived from
Sf9 insect cells infected with baculoviruses coding for TAPL
(Wolters et al., 2005). With isolated lysosomes derived from
the TAPL transduced B lymphoma cell line Raji, the lyso-
somal peptide transport activity of TAPL was proven (Demi-
rel et al., 2007). In contrast to the high affinity endoplasmic
reticulum localized peptide transporter TAP (K
m
s0.2 m
M
),
TAPL transports its peptides with low affinity (K
m
s6.8 m
M
).
With an approximate estimation, TAPL shows a turnover
number of 30 peptides per minute which is comparable to
other ABC transporters. Moreover, TAPL is an active trans-
porter accumulating peptides up to 60-fold against a gradient
(Wolters et al., 2005).
The peptide specificity was analyzed with the aid of ran-
domized peptide libraries which bear the advantage to be
independent on a special peptide sequence. TAPL shows a
broad peptide length specificity ranging from 6-mer up to
59-mer peptides, the longest peptides tested so far, with an
optimum of 23-mer peptides. For peptide recognition, side
chain as well as backbone interactions, including free N- and
C-termini, are important (Wolters et al., 2005). The influence
of single residues on the peptide specificity was analyzed
with the aid of reconstituted TAPL to reduce background
effects from crude membranes. The side chain specificity is
restricted to the N-terminal and C-terminal residue inde-
pendent of the length of the transported peptide. Positively
charged residues or large hydrophobic residues at the termini
are favored, whereas negatively charged residues or methi-
onine and asparagine at the termini are not favored residues.
Because positively charged peptides independent of the posi-
tion of the charge are preferred substrates, it seems that the
negatively charged membrane increases the concentration of
the peptides in the vicinity of the transporter (Zhao et al.,
2008). In conclusion, TAPL recognizes its peptides by the
residues on both termini. The sequence in between can be
highly promiscuous in sequence and length, ensuring that a
single transporter can translocate a large variety of different
peptides.
The side chain specificity between TAPL and TAP is very
similar (Uebel et al., 1997; Zhao et al., 2008). However,
TAPL shows broader length specificity than TAP. What can
we learn from these similarities and differences with regard
to the peptide binding pocket (PBP) of TAPL? In homology
to TAP, the PBP is predicted to comprise the cytosolic loop
between transmembrane helix 4 and helix 5 of core-TAPL
and a stretch of 15 residues following the C-terminal trans-
membrane helix of the TMD (Figure 1). In contrast to TAP
which binds only one peptide to its asymmetric PBP (Herget
et al., 2009), TAPL could bind two peptides at a time. More-
over, the broader length specificity could result from differ-
ent binding modes, using the binding site in one subunit or
bridging over between both for longer peptides.
TAPL requires ATP hydrolysis for transport because non-
hydrolyzable analogs do not drive peptide transport. The
Michaelis-Menten constant of ATP for reconstituted TAPL
(K
m,ATP
s98 m
M
) is very similar to other ABC transporters
and fits perfectly to the dissociation constant (K
d,ATP
s
90 m
M
) derived from competition assays using radio-
active labeled 8-azido-ATP as reporter (Wolters et al., 2005;
Zhao et al., 2008). The nucleotide binding pattern of TAPL
was studied by competition experiments using 8-azido-ATP
or ATP-agarose. In both studies, the purine-based nucleotides
ATP, ADP, and GTP proved to be potent in TAPL binding.
In contrast, the pyrimidine-based nucleotides CTP and UTP
show only weak affinity and AMP does not bind to TAPL
(Wolters et al., 2005; Ohara et al., 2008). This base-depend-
ent preference is also reflected in the transport activity, where
GTP shows 40%, UTP 20%, and CTP 10% of the ATP-
driven transport activity.
Functional dissection of TAPL
Based on sequence alignments, TAPL can be dissected in a
core complex (core-TAPL) composed of the six C-terminal
transmembrane helices and the NBD, showing high sequence
homology to other ABC transporters, and TMD0 with no
64 I. Bangert et al.
Article in press - uncorrected proof
Figure 2 Putative function of TAPL in antigen presentation.
Because TAPL is strongly expressed in lysosomes of professional antigen-presenting cells, we propose a function in antigen processing. In
the MHC II pathway, TAPL could transport cytosolic peptides derived from proteasomal degradation into the lumen of the MHC class II
loading compartment (MIIC) for binding to MHC class II molecules. Subsequently, loaded MHC class II molecules are shuttled to the cell
surface to expose their cargo to CD4
q
T cells. In the MHC I pathway, TAPL could display an additional cross-presentation pathway.
Exogenous antigens which are internalized by endocytosis are most probably delivered by Sec 61 to the cytosol where they are hydrolyzed
by the proteasome. Subsequently, the peptides are translocated into endosomes for binding to newly synthesized MHC class I molecules or
into lysosomes for loading onto recycled MHC class I molecules. MHC class I molecules are transferred to the cell surface of antigen-
presenting cells to activate CD8
q
cytotoxic T cells.
obvious sequence homology to any protein in the databases
(Figure 1). Core-TAPL (residues 143–766) is sufficient to
dimerize and is also active in peptide transport (Kamakura
et al., 2008; Demirel et al., 2010). However, it is predomi-
nantly mislocalized at the plasma membrane as shown by
immunofluorescence microscopy and surface biotinylation.
In contrast, TMD0 alone is targeted to the lysosomal com-
partment just as wild-type (wt)-TAPL. TMD0 does not form
homodimers or heterodimers with wt-TAPL. Interestingly,
upon coexpression of the split variants, TMD0 interacts non-
covalently with the core complex and targets it to lysosomes.
A single TMD0 per complex is sufficient for lysosomal
localization, because coexpression of wt- and core-TAPL
redirects the core complex into lysosomes (O
¨. Demirel and
R. Abele, unpublished results). Taken together, TMD0 is
essential and sufficient for the lysosomal localization of
TAPL and recruits the core complex to lysosomes.
Acidic, tyrosine-based and dileucine-based lysosomal tar-
geting motifs, all localized in the cytosolic domain of lyso-
somal membrane proteins, are described (Bonifacino and
Traub, 2003). However, in TMD0, a putative acidic and tyro-
sine-based motif is found in a transmembrane helix and a
lysosomal loop, respectively, and, therefore, cannot be con-
sidered. Furthermore, two cytosolic membrane-proximal,
vicinal leucines do not serve as targeting motifs because
mutagenesis to alanines did not affect the lysosomal locali-
zation of TAPL (Demirel et al., 2010). Therefore, the ques-
tion arises whether TAPL comprises a cryptic lysosomal
targeting motif or is it escorted into lysosomes by binding to
other lysosomal proteins as found for MHC class II mole-
cules which are accompanied by the invariant chain (Bakke
and Dobberstein, 1990; Lotteau et al., 1990).
Physiological function of TAPL
Based on the broad tissue distribution of TAPL expression
under the control of the ubiquitous active SP1 promoter, it
can be assumed that TAPL takes over a housekeeping func-
tion clearing the cytosol from accumulating peptides, thus
protecting the cell from cytotoxic effects. Furthermore, in
long-living cells, such as muscle cells and neurons or liver
and Sertoli cells with a high metabolic activity, the expres-
sion of TAPL could be elevated to deal with cytosolic pep-
The lysosomal polypeptide transporter TAPL 65
Article in press - uncorrected proof
tides to prevent premature cell death. In some cells, however,
TAPL and its orthologs seem to be involved in more spe-
cialized functions.
Recently, it was reported that the closest homologs in the
nematode Caenorhabditis elegans are the ABC transporters
HAF-4 and HAF-9 with a sequence identity of 38% to
human TAPL (Kawai et al., 2009). Both half-transporters are
expressed in non-acidic, lysosomal-associated membrane
protein positive intestinal large granules (diameter )2m
M
)
from larval to adult state. Animals homozygous for a defect
in one of these genes showed strong decreased number of
these large granules in the middle intestinal cells close to the
vulva of the hermaphrodites throughout the larval and young
adult stage. This phenotype was not observed any longer for
adults older than 1 week. Interestingly, the wt phenotype
could be restored by transfecting the animals with the miss-
ing half-transporter. However, wt N2 strain transfected with
an inactive HAF-4 variant showed decreased number of large
intestinal granules indicating that the overexpressed, inactive
mutant has a dominant-negative effect. It can be speculated
that these large granules in the intestine, which display the
nutrient interface, main energy store, and first line of
defense, function as a peptide storage compartment which
disappears if not filled by active transport. The lack of stored
peptides, which could serve as energy but also as amino acid
source for the synthesis of proteins, could also explain the
reduced brood size, slower growth, and longer defecation
cycles of deletion strain in comparison to wt animals.
The strong expression of the polypeptide transporter TAPL
in professional antigen presenting cells such as macrophages
and dendritic cells indicates a function of this transporter in
antigen presentation (Demirel et al., 2007). It was shown in
TAP-deficient fibroblasts that TAPL cannot restore TAP defi-
ciency as expected because TAPL resides in lysosomes
which are not part of the classical MHC I pathway presenting
peptides from cytosolic antigens. We can therefore speculate
two scenarios in which TAPL is involved: for negative selec-
tion of T cells during their development in the thymus and
also to suppress autoreactivity in the periphery, mainly den-
dritic cells display peptides derived from cytosolic and nucle-
ar proteins on MHC class II molecules (Jacobson et al., 1989;
Rudensky et al., 1991). In addition to different autophagy
pathways, TAPL could also account for this process, because
it was demonstrated that peptides of microinjected ovalbu-
min are presented on the cell surface by MHC class II in a
proteasome-dependent but TAP-independent pathway (Dani
et al., 2004). This additional pathway could increase the
diversity of antigenic peptides because TAPL substrates are
generated by the cytosolic proteasome, whereas antigens
delivered by macroautophagy or chaperone-mediated auto-
phagy are processed by lysosomal proteases (Figure 2).
In the process of cross-presentation, antigens are taken up
by endo- or pinocytosis. Subsequently, several pathways
seem to exist for processing of exogenous antigens and load-
ing of MHC class I molecules (Burgdorf and Kurts, 2008).
In a TAP-dependent pathway, the antigens are exported by a
cryptic transport mechanism from the lumen of the endo-
somes into the cytosol where the antigens are processed by
the proteasome. Subsequently, the peptides are transported
via TAP into endosomes or the endoplasmic reticulum for
loading of newly synthesized MHC class I molecules. How-
ever, there is also a TAP-independent pathway, in which anti-
genic peptides of exogenous proteins are loaded in lysosomes
onto recycling MHC class I molecules. TAPL could be
thought to function as a transporter delivering the peptides
into lysosomes and additionally to TAP into endosomes.
Acknowledgments
We thank Christine Le Gal for preparing the manuscript. This
research is supported by the German Research Foundation (SFB
807, I.B., F.T., and R.A.).
References
Abele, R. and Tampe´, R. (2009). Peptide trafficking and transloca-
tion across membranes in cellular signaling and self-defense
strategies. Curr. Opin. Cell Biol. 21, 508–515.
Allikmets, R., Gerrard, B., Hutchinson, A., and Dean, M. (1996).
Characterization of the human ABC superfamily: isolation and
mapping of 21 new genes using the expressed sequence tags
database. Hum. Mol. Genet. 5, 1649–1655.
Bakke, O. and Dobberstein, B. (1990). MHC class II-associated
invariant chain contains a sorting signal for endosomal com-
partments. Cell 63, 707–716.
Bonifacino, J.S. and Traub, L.M. (2003). Signals for sorting of
transmembrane proteins to endosomes and lysosomes. Annu.
Rev. Biochem. 72, 395– 447.
Borst, P. and Elferink, R.O. (2002). Mammalian ABC transporters
in health and disease. Annu. Rev. Biochem. 71, 537–592.
Burgdorf, S. and Kurts, C. (2008). Endocytosis mechanisms and the
cell biology of antigen presentation. Curr. Opin. Immunol. 20,
89–95.
Dahle, M.K., Gronning, L.M., Cederberg, A., Blomhoff, H.K., Miu-
ra, N., Enerback, S., Tasken, K.A. and Tasken, K. (2002). Mech-
anisms of FOXC2- and FOXD1-mediated regulation of the RI
asubunit of cAMP-dependent protein kinase include release of
transcriptional repression and activation by protein kinase Ba
and cAMP. J. Biol. Chem. 277, 22902–22908.
Dani, A., Chaudhry, A., Mukherjee, P., Rajagopal, D., Bhatia, S.,
George, A., Bal, V., Rath, S., and Mayor, S. (2004). The pathway
for MHCII-mediated presentation of endogenous proteins
involves peptide transport to the endo-lysosomal compartment.
J. Cell Sci. 117, 4219–4230.
Dean, M., Rzhetsky, A., and Allikmets, R. (2001). The human ATP-
binding cassette (ABC) transporter superfamily. Genome Res.
11, 1156–1166.
Demirel, O
¨., Waibler, Z., Kalinke, U., Gru¨nebach, F., Appel, S.,
Brossart, P., Hasilik, A., Tampe´, R., and Abele, R. (2007). Iden-
tification of a lysosomal peptide transport system induced during
dendritic cell development. J. Biol. Chem. 282, 37836–37843.
Demirel, O
¨., Bangert, I., Tampe´, R., and Abele, R. (2010). Tuning
the cellular trafficking of the lysosomal peptide transporter
TAPL by its N-terminal domain. Traffic 11, 383–393.
Denny, P., Swift, S., Connor, F., and Ashworth, A. (1992). An SRY-
related gene expressed during spermatogenesis in the mouse
encodes a sequence-specific DNA-binding protein. EMBO J. 11,
3705–3712.
66 I. Bangert et al.
Article in press - uncorrected proof
Herget, M., Kreissig, N., Kolbe, C., Scholz, C., Tampe´, R., and
Abele, R. (2009). Purification and reconstitution of the antigen
transport complex TAP: a prerequisite for determination of pep-
tide stoichiometry and ATP hydrolysis. J. Biol. Chem. 284,
33740–33749.
Higgins, C.F. (1992). ABC transporters: from microorganisms to
man. Annu. Rev. Cell Biol. 8, 67–113.
Jacobson, S., Sekaly, R.P., Jacobson, C.L., McFarland, H.F., and
Long, E.O. (1989). HLA class II-restricted presentation of cyto-
plasmic measles virus antigens to cytotoxic T cells. J. Virol. 63,
1756–1762.
Jones, P.M. and George, A.M. (2004). The ABC transporter struc-
ture and mechanism: perspectives on recent research. Cell. Mol.
Life Sci. 61, 682–699.
Kamakura, A., Fujimoto, Y., Motohashi, Y., Ohashi, K., Ohashi-
Kobayashi, A., and Maeda, M. (2008). Functional dissection of
transmembrane domains of human TAP-like (ABCB9). Bio-
chem. Biophys. Res. Commun. 377, 847–851.
Kawai, H., Tanji, T., Shiraishi, H., Yamada, M., Iijima, R., Inoue,
T., Kezuka, Y., Ohashi, K., Yoshida, Y., Tohyama, K., et al.
(2009). Normal formation of a subset of intestinal granules in
Caenorhabditis elegans requires ATP-binding cassette trans-
porters HAF-4 and HAF-9, which are highly homologous to
human lysosomal peptide transporter TAP-like. Mol. Biol. Cell
20, 2979–2990.
Kobayashi, A., Kasano, M., Maeda, T., Hori, S., Motojima, K.,
Suzuki, M., Fujiwara, T., Takahashi, E., Yabe, T., Tanaka, K., et
al. (2000). A half-type ABC transporter TAPL is highly con-
served between rodent and man, and the human gene is not
responsive to interferon-gin contrast to TAP1 and TAP2. J. Bio-
chem. (Tokyo) 128, 711–718.
Kobayashi, A., Hori, S., Suita, N., and Maeda, M. (2003). Gene
organization of human transporter associated with antigen proc-
essing-like (TAPL, ABCB9): analysis of alternative splicing var-
iants and promoter activity. Biochem. Biophys. Res. Commun.
309, 815–822.
Leveson-Gower, D.B., Michnick, S.W., and Ling, V. (2004). Detec-
tion of TAP family dimerizations by an in vivo assay in mam-
malian cells. Biochemistry 43, 14257– 14264.
Li, P., He, X., Gerrero, M.R., Mok, M., Aggarwal, A., and Rosen-
feld, M.G. (1993). Spacing and orientation of bipartite DNA-
binding motifs as potential functional determinants for POU
domain factors. Genes Dev. 7, 2483–2496.
Lotteau, V., Teyton, L., Peleraux, A., Nilsson, T., Karlsson, L.,
Schmid, S.L., Quaranta, V., and Peterson, P.A. (1990). Intracel-
lular transport of class II MHC molecules directed by invariant
chain. Nature 348, 600–605.
Ohara, T., Ohashi-Kobayashi, A., and Maeda, M. (2008). Biochem-
ical characterization of transporter associated with antigen pro-
cessing (TAP)-like (ABCB9) expressed in insect cells. Biol.
Pharm. Bull. 31, 1–5.
Overdier, D.G., Porcella, A., and Costa, R.H. (1994). The DNA-
binding specificity of the hepatocyte nuclear factor 3/forkhead
domain is influenced by amino-acid residues adjacent to the rec-
ognition helix. Mol. Cell. Biol. 14, 2755– 2766.
Pontiggia, A., Rimini, R., Harley, V.R., Goodfellow, P.N., Lovell-
Badge, R., and Bianchi, M.E. (1994). Sex-reversing mutations
affect the architecture of SRY-DNA complexes. EMBO J. 13,
6115–6124.
Rudensky, A., Preston-Hurlburt, P., Hong, S.C., Barlow, A., and
Janeway, C.A., Jr. (1991). Sequence analysis of peptides bound
to MHC class II molecules. Nature 353, 622–627.
Schmitt, L. and Tampe´, R. (2000). Affinity, specificity, diversity: a
challenge for the ABC transporter TAP in cellular immunity.
ChemBioChem 1, 16–35.
Schmitt, L. and Tampe´, R. (2002). Structure and mechanism of ABC
transporters. Curr. Opin. Struct. Biol. 12, 754–760.
Uebel, S., Kraas, W., Kienle, S., Wiesmuller, K.H., Jung, G., and
Tampe´, R. (1997). Recognition principle of the TAP transporter
disclosed by combinatorial peptide libraries. Proc. Natl. Acad.
Sci. USA 94, 8976–8981.
Uinuk-ool, T.S., Mayer, W.E., Sato, A., Takezaki, N., Benyon, L.,
Cooper, M.D., and Klein, J. (2003). Identification and charac-
terization of a TAP-family gene in the lamprey. Immunogenetics
55, 38–48.
Wolters, J.C., Abele, R., and Tampe´, R. (2005). Selective and ATP-
dependent translocation of peptides by the homodimeric ATP
binding cassette transporter TAP-like (ABCB9). J. Biol. Chem.
280, 23631–23636.
Yamaguchi, Y., Kasano, M., Terada, T., Sato, R., and Maeda, M.
(1999). An ABC transporter homologous to TAP proteins. FEBS
Lett. 457, 231–236.
Yamaguchi, Y., Iseoka, H., Kobayashi, A., and Maeda, M. (2004).
The carboxyl-terminal sequence of rat transporter associated
with antigen processing (TAP)-like (ABCB9) is heterogeneous
due to splicing of its mRNA. Biol. Pharm. Bull. 27, 100–104.
Young, L., Leonhard, K., Tatsuta, T., Trowsdale, J., and Langer, T.
(2001). Role of the ABC transporter Mdl1 in peptide export
from mitochondria. Science 291, 2135–2138.
Zhang, F., Zhang, W., Liu, L., Fisher, C.L., Hui, D., Childs, S.,
Dorovini-Zis, K., and Ling, V. (2000). Characterization of
ABCB9, an ATP binding cassette protein associated with lyso-
somes. J. Biol. Chem. 275, 23287–23294.
Zhao, C., Haase, W., Tampe´, R., and Abele, R. (2008). Peptide spec-
ificity and lipid activation of the lysosomal transport complex
ABCB9 (TAPL). J. Biol. Chem. 283, 17083–17091.
Received August 27, 2010; accepted October 6, 2010
