A0A2R9CAF4 is the full-length (606 aa) product of the bonobo SLC26A11 gene (KBAT, kidney and brain anion transporter), a member of the SLC26/SulP anion transporter family with a 14-helix transmembrane domain and a C-terminal cytosolic STAS domain. It is 99.2% identical to human SLC26A11 over its full length and retains the pH-sensing glutamate (Glu-320 in human). Human SLC26A11 forms a homodimer with domain-swapped STAS domains and is a dual-function protein. As a secondary active transporter it couples the symport of one proton and one sulfate ion to the antiport of one chloride ion, an electroneutral cycle that is selective for sulfate over bicarbonate and phosphate. During this transport cycle it can also enter an uncoupled, channel-like chloride-conducting state. In mammalian cell lines the protein resides mainly in the lysosomal membrane, where the luminal acid gradient favours proton-driven sulfate efflux; it is proposed to be the lysosomal sulfate exporter that removes sulfate released during catabolism of sulfated macromolecules. A plasma membrane pool is seen in some cells and tissues, for example apically and basolaterally in renal collecting duct intercalated cells and in cerebellar Purkinje neurons. Plasmalemmal SLC26A11 chloride currents have been linked to neuronal chloride entry and swelling under hypoxia. The gene is broadly expressed, with highest levels in brain, kidney and placenta.
Summary: Transferred from human SLC26A11 (Q86WA9), the one-to-one ortholog (99.2% identity, same CTD gene id). Human SLC26A11 localizes to lysosomes in various mammalian cell lines, and its transport properties match the lysosomal sulfate efflux problem.
Reason: Lysosomal membrane is the main functional location of SLC26A11 in mammalian cells, and the orthology to human SLC26A11 is unambiguous.
Bonobo vs human: 601/606 identical aligned positions (99.2%), no gaps; full-length product, not a fragment.
GO:0008271 secondary active sulfate transmembrane transporter activity
IEA GO_REF:0000002
MODIFY
Summary: InterPro mapping (IPR018045, SLC26A sulfate transporter signature). The term is correct: purified human SLC26A11 reconstituted in proteoliposomes performs proton-coupled sulfate transport. The demonstrated mechanism is more specific: symport of one proton with one sulfate ion, coupled to chloride antiport. The child term sulfate:proton symporter activity (GO:0008512, is_a GO:0008271) captures the proton coupling that the evidence supports.
Reason: Correct but less specific than the evidence. The more specific supported descendant is sulfate:proton symporter activity. The pH-sensing residue Glu-320 that couples protons to sulfate binding is conserved in the bonobo protein.
In the most parsimonious model, SLC26A11 is an exchanger that couples the symport of one proton and one sulfate ion (net charge of β1) to the antiport of one chloride ion (net charge of β1).
Summary: ARBA-derived. True (sulfate and chloride are inorganic anions) but general; the gene already carries the specific processes sulfate transmembrane transport and chloride transmembrane transport.
Reason: Correct but general; replace with the specific descendants already annotated to this gene and supported by direct evidence for the human ortholog.
Summary: True for a multipass SLC26 transporter (Phobius predicts transmembrane helices), but uninformative; the specific membrane is the lysosomal membrane, which this gene already carries.
Reason: Correct but general. Replace with lysosomal membrane, the supported specific location already annotated to this gene.
Summary: Derives from mouse Slc26a11 (Q80ZD3; same PANTHER subfamily PTHR11814:SF55 as human SLC26A11). Immunostaining of mouse kidney showed Slc26a11 with the V-ATPase on the basolateral membrane of B-intercalated cells in the cortical collecting duct. This is a real but cell-type-restricted pool; in cultured mammalian cells the protein is mainly lysosomal, and plasma membrane delivery varies between cell types.
Reason: Supported by in vivo tissue localization of the mouse ortholog, but it is a tissue-specific surface pool, not the main site of the conserved sulfate export function.
KBAT and H+-ATPase colocalize on the apical membrane of A-intercalated cells and on the basolateral membrane of B-intercalated cells in the cortical collecting duct
Summary: Derives from mouse Slc26a11. In mouse kidney Slc26a11 co-localizes with the V-ATPase on the apical membrane of A-intercalated cells, and is exclusively apical in the medullary collecting duct. As with the basolateral pool, this is a cell-type-specific surface location.
Reason: Experimentally observed in mouse kidney intercalated cells, but peripheral to the conserved lysosomal function.
KBAT and H+-ATPase colocalize on the apical membrane of A-intercalated cells and on the basolateral membrane of B-intercalated cells in the cortical collecting duct
Summary: InterPro mapping (IPR001902). True but very general; the specific processes are sulfate and chloride transmembrane transport, both annotated to this gene. The PAINT IBD for sulfate transmembrane transport (PTN000212046) includes human SLC26A11 among its descendant evidence.
Reason: Correct but general; replace with the specific supported descendants already on this gene.
GO:0098656 monoatomic anion transmembrane transport
IEA GO_REF:0000108
MODIFY
Summary: Inferred by GO logic from monoatomic anion transmembrane transporter activity. Sulfate is polyatomic, so this term is supported only by chloride movement (counter-transport and channel-like conductance). The specific supported descendant is chloride transmembrane transport.
Reason: Correct but general; the monoatomic anion moved is chloride, so replace with chloride transmembrane transport, already on this gene.
Summary: Core process. Human SLC26A11 transports sulfate in proteoliposomes and in cells, and a PAINT IBD for this term sits at PANTHER node PTN000212046, with human SLC26A11 (Q86WA9) among the descendant evidence. The bonobo protein is a near-identical one-to-one ortholog.
Reason: Direct biochemical evidence for the human ortholog plus phylogenetic support from the PAINT node covering the SLC26A11 lineage.
Summary: Inferred from chloride channel activity. SLC26A11 moves chloride both as the antiported ion of its electroneutral transport cycle and through an uncoupled chloride-conducting state. Chloride conductance was also measured for mouse Slc26a11 in HEK293 cells and for neuronal SLC26A11 under hypoxia.
Reason: Directly demonstrated for human and mouse orthologs; chloride transport is an intrinsic part of the transport cycle and of the channel mode.
Summary: Ensembl Compara transfer from mouse Slc26a11. Patch clamp of mouse Slc26a11 in HEK293 cells showed a basally active chloride channel, and purified human SLC26A11 shows an uncoupled chloride conductance that arises from the proton:sulfate transport cycle. This channel mode is a genuine, if unusual, activity of the same protein.
Reason: Demonstrated by electrophysiology for both mouse and human orthologs and explained mechanistically by the human structure-function study.
Summary: Ensembl transfer from human Q86WA9. ER signal is expected for a glycosylated multipass membrane protein in biosynthetic transit. No study places a functional SLC26A11 pool in the ER, and the protein's steady-state location in mammalian cells is the lysosome.
Reason: Likely reflects biosynthetic transit rather than a site where the protein acts.
Summary: Ensembl transfer from human Q86WA9. SLC26A11 is thought to pass from the trans-Golgi network to the plasma membrane and then to lysosomes, so a Golgi signal is expected in transit. No evidence places a functional pool in the Golgi.
Reason: Transit compartment on the route to lysosomes, not a functional location.
Its appearance at the cell surface suggests that it is first trafficked from the trans-Golgi network to the plasma membrane and subsequently delivered to the lysosome following internalization
Summary: Human SLC26A11 reached the cell membrane in COS-7 and Sf9 cells, mouse Slc26a11 is plasmalemmal in Purkinje cells and in kidney intercalated cells, and plasmalemmal SLC26A11 provides a chloride entry route in hypoxic neurons. The plasma membrane pool is real but varies with cell type, and the main location in cultured mammalian cells is the lysosome.
Reason: Experimentally supported secondary location. It is as precise as warranted outside polarized epithelia (Purkinje neurons, cultured cells) and is peripheral to the lysosomal sulfate export function.
Compared to its lysosomal counterpart, SLC26A11 residing in the plasma membrane is less likely to reach the chloride-conductive state under physiological conditions.
Summary: ARBA plus human ortholog transfer. Sulfate is polyatomic, so only the chloride activity supports this term. Chloride channel activity (GO:0005254) is an is_a descendant of this term and is already annotated to this gene.
Reason: Correct but general; the specific supported descendant is chloride channel activity, already on this gene.
Summary: Ensembl transfer from mouse Slc26a11. The mouse source evidence is a pHi recovery assay in transiently transfected COS7 cells, interpreted as chloride/bicarbonate exchange. In the later study with purified human SLC26A11 reconstituted in proteoliposomes, bicarbonate did not compete with sulfate transport, and the exchange cycle couples proton:sulfate symport to chloride antiport. The bicarbonate exchange mode therefore rests on an indirect cellular assay and is not supported by the direct biochemistry.
Reason: Disputed activity. The only support is an indirect cellular assay of the mouse ortholog, and direct reconstitution of the human ortholog found no bicarbonate interaction. It is not removed because the mouse experimental claim has not been formally refuted in mouse protein, but it should not be propagated as a core activity.
Taken together, these results are consistent with KBAT functioning in the ClββHCO3β exchange mode.
Core Functions
Proton-coupled sulfate transport across the lysosomal membrane: electroneutral symport of one proton and one sulfate ion coupled to antiport of one chloride ion, using the lysosomal acid gradient to export sulfate.
In the most parsimonious model, SLC26A11 is an exchanger that couples the symport of one proton and one sulfate ion (net charge of β1) to the antiport of one chloride ion (net charge of β1).
Uncoupled, channel-like chloride conductance that arises from the proton:sulfate transport cycle. It is most likely to be reached in the acidic lysosome; plasma membrane pools in neurons and transfected cells also conduct chloride.
Q: Is the Cl-/HCO3- exchange reported for mouse Slc26a11 in COS7 cells (Ensembl source of GO:0140900) reproducible with purified mouse protein, or does it reflect an indirect effect on endogenous transport, given that purified human SLC26A11 shows no bicarbonate interaction?
Q: GO has no process term for sulfate export from the lysosome to the cytosol; would a term such as lysosomal sulfate export be useful for SLC26A11 and similar lysosomal catabolite exporters?
Suggested Experiments
Experiment: Measure lysosomal sulfate content and sulfatase substrate clearance in SLC26A11 knockout cells, to test in cells the proposed role as the lysosomal sulfate exporter.
Experiment: Reconstitute purified mouse Slc26a11 and test bicarbonate-dependent chloride flux directly, to resolve the conflict between the cellular and reconstitution data.
External Prediction Reviews
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.
A0A2R9CAF4 is the bonobo SLC26A11 (KBAT) product, a one-to-one ortholog of human SLC26A11 (99.2% identity). Human SLC26A11 is a lysosomal proton/sulfate:chloride transporter that also conducts chloride in a channel-like state. Both ProtNLM2 terms are correct but less precise than supported annotations the gene already carries (chloride channel activity; lysosomal membrane).
LSP β Less precise than existing annotation Review score: 2/2
Prediction method: ProtNLM2 Β· Version: UniProt 2024_06 pilot
Review rationale: The target is the full-length bonobo ortholog of human SLC26A11 (99.2% identical, no gaps), with the SLC26/SulP transmembrane domain and a C-terminal STAS domain. SLC26A11 conducts chloride: the human protein shows an uncoupled, channel-like chloride conductance (PMID:42509233), and mouse KBAT functions as a constitutively active chloride channel (PMID:23733100). Chloride conduction supports monoatomic anion transmembrane transporter activity; sulfate, the other substrate, is polyatomic and does not. The gene already carries the more specific supported descendant chloride channel activity (GO:0005254), so the prediction is correct 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: "exhibits an uncoupled, channel-like chloride conductance gated by proton:sulfate"
PMID:23733100: "We further demonstrate that KBAT can function as a constitutively active chloride channel."
LSP β Less precise than existing annotation Review score: 2/2
Prediction method: ProtNLM2 Β· Version: UniProt 2024_06 pilot
Review rationale: The target has multiple predicted transmembrane segments, so membrane residence is supported by sequence architecture. Human SLC26A11, its one-to-one ortholog, localizes to lysosomes in mammalian cell lines (PMID:42509233), and the gene already carries the supported lysosomal membrane term (GO:0005765), an is_a descendant of membrane. Membrane is correct 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: "SLC26A11 exclusively localizes to lysosomes in various mammalian cell lines"