A0A2R9CAF4 is the bonobo (Pan paniscus) ortholog of human SLC26A11 (also known as KBAT, kidney and brain anion transporter), a member of the SLC26/SulP transporter family. SLC26A11 is a dual-function protein that operates both as an electroneutral proton-coupled sulfate/chloride exchanger and as a chloride-selective channel. The transporter contains a transmembrane domain with 14 helices arranged in two inverted repeats and a cytosolic STAS (Sulfate Transporter and Anti-Sigma factor antagonist) domain. It functions as a homodimer. The primary physiological role is lysosomal sulfate export: the protein uses the lysosomal proton gradient to selectively transport sulfate from the acidic lysosomal lumen to the cytoplasm, preventing product inhibition of lysosomal sulfatases. A unique glutamate residue (Glu-320 in human) serves as a pH-sensitive switch that increases sulfate binding affinity approximately 50-fold at acidic pH, enabling selective sulfate transport despite much higher luminal chloride concentrations. The protein is broadly expressed, with highest levels in brain and kidney, consistent with a housekeeping role in lysosomal catabolite clearance. Under pathological acidic conditions (e.g., brain ischemia), plasmalemmal SLC26A11 chloride channel activity may contribute to cytotoxic neuronal swelling.
Summary: Multiple independent studies from 2024-2025 establish that SLC26A11 localizes predominantly to lysosomes in mammalian cells. Confocal microscopy with fluorescently tagged SLC26A11 in HEK293T, COS1, CHO, and renal intercalated cells shows significant overlap with the lysosomal marker Lamp1 (Manders coefficient 0.45-0.50). Both mouse and human orthologs show similar lysosomal localization. This is the primary functional location where the protein exports sulfate using the lysosomal proton gradient.
Reason: Lysosomal membrane is the primary functional location of SLC26A11, strongly supported by recent localization studies and consistent with its role as a lysosomal sulfate exporter.
GO:0008271 secondary active sulfate transmembrane transporter activity
IEA GO_REF:0000002
ACCEPT
Summary: Reconstitution experiments with purified human SLC26A11 in proteoliposomes demonstrate that it catalyzes symport of one proton with one sulfate ion coupled to antiport of one chloride ion. The transport is strongly pH-dependent, with highest sulfate accumulation at pH gradients of 2.0-2.5 units with acidic pH on the luminal side. The apparent KM for sulfate is 39.7 +/- 5.5 uM under optimal conditions. This is a core molecular function of SLC26A11.
Reason: Sulfate transporter activity is a core function of SLC26A11, directly demonstrated by reconstitution studies with purified protein.
Summary: SLC26A11 does transport inorganic anions (sulfate, chloride), so this term is technically correct. However, it is very broad and does not capture the specific transport substrates or mechanism. More informative process terms such as sulfate transmembrane transport (GO:1902358) are also annotated.
Reason: Correct but too general to be informative when more specific transport process annotations are present.
Summary: SLC26A11 is indeed an integral membrane protein with 10 predicted transmembrane helices (per Phobius) and 14 TM helices in the cryo-EM structure. However, the term 'membrane' is extremely broad and adds no information beyond what is conveyed by the more specific lysosomal membrane annotation.
Reason: The generic 'membrane' term is redundant with the more specific lysosomal membrane (GO:0005765) and plasma membrane (GO:0005886) annotations.
Summary: This annotation is transferred from the mouse ortholog Q80ZD3 via Ensembl. However, recent 2024 localization studies show that SLC26A11 predominantly localizes to lysosomes in multiple mammalian cell types, with minimal overlap with plasma membrane markers. The basolateral plasma membrane annotation likely derives from older immunohistochemistry studies in kidney intercalated cells that may have detected the protein in transit through the secretory pathway or at low levels on the plasma membrane. The primary functional location is the lysosomal membrane.
Reason: Recent comprehensive localization studies demonstrate predominant lysosomal localization. Basolateral plasma membrane is not the primary functional location and likely represents a minor or transient pool.
Summary: Like the basolateral annotation, this is transferred from the mouse ortholog. The same concerns apply: SLC26A11 predominantly localizes to lysosomes, not to the apical plasma membrane. The 2024 Bungert-Plumke et al. study showed that SLC26A11 localization is independent of cell type and consistently intracellular/lysosomal.
Reason: SLC26A11 predominantly localizes to lysosomes. Apical plasma membrane is not the primary functional location based on recent localization data.
Summary: SLC26A11 is a transmembrane transporter, so involvement in transmembrane transport is correct. However, this is a very broad parent term that adds little information when more specific process terms (sulfate transmembrane transport, chloride transmembrane transport) are annotated.
Reason: Correct but too general; subsumed by the more specific sulfate and chloride transmembrane transport annotations.
GO:0098656 monoatomic anion transmembrane transport
IEA GO_REF:0000108
KEEP AS NON CORE
Summary: This was inferred from monoatomic anion transmembrane transporter activity (GO:0008509) via logical inference. SLC26A11 does transport monoatomic anions (chloride, sulfate). The term is correct but represents an intermediate level of specificity between the very broad transmembrane transport and the specific sulfate/chloride transport annotations.
Reason: Logically inferred and correct, but redundant with more specific transport process annotations.
Summary: Sulfate transmembrane transport is the primary biological process mediated by SLC26A11. The protein functions as the lysosomal sulfate exporter, using the proton gradient to drive sulfate from the acidic lysosomal lumen to the cytoplasm. This prevents product accumulation that would inhibit lysosomal sulfatases. Reconstitution studies confirm direct sulfate transport with KM of approximately 40 uM.
Reason: This is the core biological process of SLC26A11, directly supported by functional reconstitution studies.
Summary: This was inferred from chloride channel activity (GO:0005254). SLC26A11 does conduct chloride, both as the counter-ion in sulfate/chloride exchange and through its chloride channel mode. The chloride channel activity is gated by proton and sulfate transport. Under physiological lysosomal conditions, chloride fluxes may help maintain lysosomal chloride homeostasis.
Reason: Chloride transport occurs as part of the coupled sulfate/chloride exchange mechanism and through the channel mode, but is secondary to the primary sulfate export function. The annotation is valid but represents a supporting rather than core activity.
Summary: SLC26A11 does exhibit chloride-selective channel conductance, as demonstrated by whole-cell patch clamp experiments. The channel activity is gated by conditions favoring sulfate binding and transport, with current reversal potentials near the Nernst equilibrium potential for chloride. This dual transporter-channel behavior is well-established for SLC26A11 and places it among a small group of transporters with both coupled transport and channel-like properties. The annotation is transferred from the mouse ortholog via Ensembl.
Reason: Chloride channel activity is a genuine molecular function of SLC26A11, directly demonstrated by electrophysiology. The dual transporter-channel mechanism is a distinctive feature of this protein.
Summary: This annotation is transferred from the human ortholog Q86WA9 via Ensembl. The 2024 Bungert-Plumke et al. study specifically showed minimal overlap between SLC26A11 and the ER marker calnexin (Manders coefficient 0.09-0.12). Some ER localization is expected for any integral membrane protein in transit through the secretory pathway, but the ER is not a functional location for SLC26A11.
Reason: ER localization is minimal and likely reflects transient biosynthetic trafficking rather than functional residence. Recent studies explicitly show low overlap with ER markers.
Summary: Transferred from the human ortholog via Ensembl. Like the ER annotation, Golgi localization likely reflects transit through the secretory pathway en route to lysosomes rather than functional residence. The 2024 localization studies consistently show predominant lysosomal localization across multiple cell types.
Reason: Golgi localization likely represents biosynthetic trafficking to lysosomes rather than the functional site of this protein.
Summary: SLC26A11 can reach the plasma membrane under certain conditions (e.g., in Sf9 insect cells used for electrophysiology), and a small fraction may be present on the plasma membrane in mammalian cells. However, the predominant localization is lysosomal. Plasmalemmal SLC26A11 has been implicated in pathological neuronal swelling during ischemia, but this appears to be a pathological rather than physiological context.
Reason: Plasma membrane localization is real but minor under physiological conditions. The primary functional location is the lysosomal membrane. The plasma membrane pool becomes pathologically relevant during ischemia.
Summary: SLC26A11 transports sulfate (SO4 2-), chloride (Cl-), oxalate, thiosulfate, selenate, and other anions, so this broad transporter activity term is correct. However, more specific molecular function terms (secondary active sulfate transmembrane transporter activity, chloride channel activity, chloride:bicarbonate antiporter activity) are also annotated and provide much more information about the actual transport mechanism.
Reason: Correct as a broad classification but redundant with more specific molecular function annotations.
Summary: This annotation is transferred from the mouse ortholog via Ensembl. Early literature proposed that SLC26A11 mediates chloride-bicarbonate exchange in kidney. However, recent 2025 reconstitution studies with purified SLC26A11 showed that bicarbonate shows little to no competition for the substrate binding site. The primary exchange mechanism is proton-coupled sulfate/chloride exchange, not chloride/bicarbonate antiport. This may represent an older functional characterization that has been superseded by more recent direct biochemical evidence.
Reason: Recent direct biochemical evidence indicates bicarbonate is not a significant substrate. The actual mechanism is proton-coupled sulfate/chloride exchange. The term should be replaced with a more accurate description of the exchange activity.
Lysosomal sulfate export: SLC26A11 mediates electroneutral proton-coupled sulfate/chloride exchange across the lysosomal membrane, exporting sulfate released by lysosomal sulfatase activity to prevent product inhibition. This is the primary housekeeping function of the protein.
Chloride channel activity: SLC26A11 has a chloride-selective channel mode gated by proton and sulfate transport. Under physiological conditions in lysosomes, this may contribute to chloride homeostasis. Under pathological acidification (e.g., brain ischemia), plasmalemmal SLC26A11 chloride currents can contribute to cytotoxic neuronal swelling.
These computational predictions are reviewed separately from the GOA annotation set used for this review. The assessments below are from this project and do not constitute official GO annotations or endorsement by GO/UniProt. They are not included in the existing annotation review above.
The SLC26-family membrane architecture supports anion transport. Both predictions are broader than existing specific transport or membrane-localization annotations.
LSP — Less precise than existing annotation Review score: 2/2
Prediction method: ProtNLM2 · Version: UniProt 2024_06 pilot
Review rationale: The target has the SLC26/SulP transport domain, multiple transmembrane segments, and a STAS domain. Experimental characterization of SLC26A11 supports chloride conduction as well as sulfate transport (PMID:42509233), providing family-level grounding for anion transport. The cached target annotations include the more specific chloride channel activity. The generic anion-transporter prediction is therefore supported but less precise.
Supporting Evidence:
file:PANPA/A0A2R9CAF4/A0A2R9CAF4-uniprot.txt: "ID A0A2R9CAF4_PANPA Unreviewed; 606 AA. ... DR InterPro; IPR001902; SLC26A/SulP_fam. ... DR InterPro; IPR002645; STAS_dom. ... FT TRANSMEM 52..70 ... FT TRANSMEM 76..94 ... FT TRANSMEM 123..144 ... FT TRANSMEM 156..179 ... FT TRANSMEM 199..218 ... FT TRANSMEM 239..262 ... FT TRANSMEM 308..329 ... FT TRANSMEM 341..360 ... FT TRANSMEM 398..419 ... FT TRANSMEM 440..465 ... FT DOMAIN 480..564 ... FT /note="STAS""
PMID:42509233: "both a sulfate transporter and a chloride channel"
LSP — Less precise than existing annotation Review score: 2/2
Prediction method: ProtNLM2 · Version: UniProt 2024_06 pilot
Review rationale: Multiple transmembrane segments in the target provide direct sequence-architecture support for membrane residence. This agrees with the membrane transport behavior characterized for SLC26A11 (PMID:42509233). The cached annotations identify specific membranes, including lysosomal and plasma membranes. Membrane is a valid but less precise localization and is not an error merely because it is broad.
Supporting Evidence:
file:PANPA/A0A2R9CAF4/A0A2R9CAF4-uniprot.txt: "ID A0A2R9CAF4_PANPA Unreviewed; 606 AA. ... DR InterPro; IPR001902; SLC26A/SulP_fam. ... DR InterPro; IPR002645; STAS_dom. ... FT TRANSMEM 52..70 ... FT TRANSMEM 76..94 ... FT TRANSMEM 123..144 ... FT TRANSMEM 156..179 ... FT TRANSMEM 199..218 ... FT TRANSMEM 239..262 ... FT TRANSMEM 308..329 ... FT TRANSMEM 341..360 ... FT TRANSMEM 398..419 ... FT TRANSMEM 440..465 ... FT DOMAIN 480..564 ... FT /note="STAS""
PMID:42509233: "both a sulfate transporter and a chloride channel"