ABCB9

ABCB9 (TAPL) is a half-type ABC transporter that homodimerizes and functions in the membranes of lysosomes (PMID:10748049, PMID:18175933). Its N-terminal transmembrane region (Met1–Arg141) carries a lysosomal sorting signal that directs the protein to lysosomal membranes, where it concentrates in cholesterol-enriched, detergent-resistant lipid raft microdomains together with flotillin-1; the core transporter domain alone lacks targeting information and distributes broadly across intracellular membranes (PMID:18952056, PMID:21212514). The protein assembles as a homodimer in membranes and, through an N-terminal segment (M1–G75), can additionally associate with the peptide transporters TAP1 and TAP2 (PMID:15577206, PMID:18175933). ABCB9 binds purine nucleotides ATP and ADP, but not AMP or pyrimidines, in a Mg2+-dependent, pH-neutral manner (PMID:18175933), and an intact Walker A ATP-binding motif is required for its transport activity, as a Walker A mutant abolishes the valinomycin-sensitivity phenotype it confers in yeast (PMID:16554024). Expression of ABCB9 is post-transcriptionally repressed by miR-31 and miR-24, which directly target its 3'UTR; this repression modulates drug transport and contributes to cisplatin resistance in non-small-cell lung cancer and paclitaxel sensitivity in breast cancer cells (PMID:24099915, PMID:27895747). The physiological transport substrate of ABCB9 has not been identified in the available corpus.

1. 2000 Medium

   Established the subcellular home of ABCB9, answering where a newly identified half ABC transporter acts by placing it at the lysosome.

   Evidence Immunofluorescence co-localization with LAMP1/LAMP2 in transfected cells, plus Northern and phylogenetic analysis

   PMID:10748049

   Open questions at the time

   • No transport substrate identified
   • Functional transport activity not demonstrated
   • Co-localization only in overexpression context
2. 2003 Medium

   Defined the gene architecture and transcriptional control of ABCB9, showing alternative splicing of exon 12 and a GC-box-driven, TATA-less promoter.

   Evidence 3'RACE, genomic sequencing, and luciferase promoter activity assay

   PMID:13679046

   Open questions at the time

   • Functional consequence of C-terminal splice isoforms unknown
   • Transcription factors binding the GC-boxes not identified
3. 2004 Medium

   Mapped the N-terminal region as the determinant of intracellular membrane targeting and first showed self-association and interaction with TAP1/TAP2.

   Evidence Truncation analysis of GFP/DsRed fusion constructs by co-expression and co-localization imaging

   PMID:15577206

   Open questions at the time

   • TAP1/TAP2 interaction shown only by co-localization, no biochemical complex isolation
   • Functional role of TAP association undefined
4. 2006 Medium

   Demonstrated that ABCB9 is a functional transporter whose activity requires ATP binding, linking the Walker A motif to a measurable cellular phenotype.

   Evidence Heterologous expression in yeast with valinomycin sensitivity assay and Walker A mutagenesis

   PMID:16554024

   Open questions at the time

   • Endogenous substrate not identified
   • Phenotype is indirect (valinomycin sensitivity), not a direct transport measurement
5. 2008 Medium

   Characterized the nucleotide specificity and oligomeric state, establishing ABCB9 as a homodimer that selectively binds purine nucleotides.

   Evidence ATP/ADP/AMP-agarose binding with competition and chemical cross-linking of insect-cell-expressed protein

   PMID:18175933

   Open questions at the time

   • ATP hydrolysis kinetics not measured
   • Coupling of nucleotide binding to substrate transport not shown
6. 2008 Medium

   Pinpointed the lysosomal sorting signal to the N-terminal transmembrane domain (Met1–Arg141) and showed the core domain interacts with full-length protein but lacks targeting.

   Evidence Co-immunoprecipitation of tagged domain constructs and fluorescence imaging of GFP-tagged truncations

   PMID:18952056

   Open questions at the time

   • Sorting machinery recognizing the signal not identified
   • Structural basis of N-terminal/core interaction unknown
7. 2011 Medium

   Refined the localization to cholesterol-rich lipid raft microdomains of the lysosomal membrane, distinguishing it from mitochondrial localization.

   Evidence Percoll/sucrose density gradients, LysoTracker/MitoTracker co-localization, detergent resistance, and methyl-β-cyclodextrin treatment in CHO-K1 cells

   PMID:21212514

   Open questions at the time

   • Functional significance of raft localization for transport unknown
   • Performed in overexpressing stable lines
8. 2016 Medium

   Established post-transcriptional control of ABCB9 by miR-31 and miR-24 and tied its expression to chemotherapy response in cancer cells.

   Evidence 3'UTR luciferase reporter assays, miRNA over/under-expression, ABCB9 knockdown, and xenograft (miR-24)

   PMID:24099915 PMID:27895747

   Open questions at the time

   • Direct drug substrate transported by ABCB9 not defined
   • Mechanism linking ABCB9 transport activity to apoptosis/resistance unresolved

• The endogenous physiological substrate of ABCB9 and the molecular link between its lysosomal transport activity and drug resistance remain undefined.
• No transport substrate identified
• No structural model of the transporter
• Physiological lysosomal function unknown