Carbonic anhydrase 8 (CA8/CARP VIII) is a soluble carbonic-anhydrase-family protein that lacks the canonical zinc-dependent carbon dioxide hydration activity. Human CA8 carries Arg116 at a position occupied by a zinc-coordinating histidine in active family members. CA8 binds the cytoplasmic regulatory region of the endoplasmic-reticulum calcium-release channel ITPR1 and can reduce IP3 sensitivity and IP3-evoked calcium release. It is abundant in cerebellar Purkinje cells, and biallelic pathogenic variants cause congenital cerebellar ataxia with variable neurodevelopmental impairment.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004089 carbonate dehydratase activity | IEA GO_REF:0000002 | REMOVE | Summary: The catalytic annotation overextends an alpha-carbonic-anhydrase domain signature to an inactive family member. Reason: The preserved InterPro signatures describe a retained fold, but human CA8 replaces a canonical zinc ligand with Arg116. The complete PMID:8977131 abstract explicitly distinguishes inactive recombinant murine wild-type CARP from an engineered Arg117His/Glu115Gln double mutant that acquires zinc-dependent CO2 hydration. Human UniProt independently records absent carbonic anhydrase activity. The conserved target-specific catalytic-site change and biochemical contrast support removing the electronic activity assignment; this does not assert that every conceivable alternative chemical activity has been excluded. Propagation Review Root cause: PROPAGATION BAD Failure modes: PSEUDO OR SUBACTIVITY LOSS Sources checked: InterPro:IPR018338 SUPPORTS SOURCE BUT NOT TARGET The preserved alpha-carbonic-anhydrase signature identifies the family fold; the CA8 catalytic-zinc-site substitution prevents inferring the corresponding wild-type activity/site. InterPro:IPR023561 SUPPORTS SOURCE BUT NOT TARGET The preserved alpha-carbonic-anhydrase signature identifies the family fold; the CA8 catalytic-zinc-site substitution prevents inferring the corresponding wild-type activity/site. Supporting Evidence: PMID:8977131 unmodified CARP is catalytically inactive file:human/CA8/CA8-uniprot.txt PMID:32316137 CA-VIII contains an Arg residue substitution at position 116 |
| GO:0008270 zinc ion binding | IEA GO_REF:0000002 | REMOVE | Summary: The inherited catalytic zinc-site assignment is not supported for wild-type CA8. Reason: This InterPro-derived assertion accompanies the alpha-carbonic-anhydrase fold. Human CA8 lacks one canonical histidine zinc ligand, and PMID:8977131 recovered a stoichiometric zinc-protein complex from the engineered murine double mutant in contrast to unmodified CARP. These observations argue against transferring the family catalytic zinc-binding function to wild-type CA8. They do not establish an absolute inability to contact zinc at any concentration or in any unrelated experimental condition. Propagation Review Root cause: PROPAGATION BAD Failure modes: PSEUDO OR SUBACTIVITY LOSS Sources checked: InterPro:IPR018338 SUPPORTS SOURCE BUT NOT TARGET The preserved alpha-carbonic-anhydrase signature identifies the family fold; the CA8 catalytic-zinc-site substitution prevents inferring the corresponding wild-type activity/site. InterPro:IPR023561 SUPPORTS SOURCE BUT NOT TARGET The preserved alpha-carbonic-anhydrase signature identifies the family fold; the CA8 catalytic-zinc-site substitution prevents inferring the corresponding wild-type activity/site. Supporting Evidence: PMID:8977131 this double mutant was isolated as a 1:1 zinc-protein complex file:human/CA8/CA8-uniprot.txt |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: Retain the curator-supported screen interactions as non-core binding. Reason: CA8โTBX3 pair (UniProtKB:O15119) is supported by the preserved GOA assertion and matching UniProt IntAct edge. Retain as non-core with curator deference. The individual target-table cell and pair-specific orthogonal retest were not inspected; shared source-framework limits are detailed in the notes. This interaction does not establish the partnerโs function in CA8 or an ITPR1-like mechanism. |
| GO:0005515 protein binding | IPI PMID:25910212 Widespread macromolecular interaction perturbations in human... | KEEP AS NON CORE | Summary: Retain the curator-supported screen interactions as non-core binding. Reason: CA8โCRX pair (UniProtKB:O43186) is supported by the preserved GOA assertion and matching UniProt IntAct edge. Retain as non-core with curator deference. The individual target-table cell and pair-specific orthogonal retest were not inspected; shared source-framework limits are detailed in the notes. This interaction does not establish the partnerโs function in CA8 or an ITPR1-like mechanism. |
| GO:0005515 protein binding | IPI PMID:27107012 Pooled-matrix protein interaction screens using Barcode Fusi... | KEEP AS NON CORE | Summary: Retain the curator-supported screen interactions as non-core binding. Reason: CA8โHSD17B14 pair (UniProtKB:Q9BPX1) is supported by the preserved GOA assertion and matching UniProt IntAct edge. Retain as non-core with curator deference. The individual target-table cell and pair-specific orthogonal retest were not inspected; shared source-framework limits are detailed in the notes. This interaction does not establish the partnerโs function in CA8 or an ITPR1-like mechanism. |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | KEEP AS NON CORE | Summary: Retain the curator-supported screen interactions as non-core binding. Reason: CA8โCRX pair (UniProtKB:O43186) is supported by the preserved GOA assertion and matching UniProt IntAct edge. Retain as non-core with curator deference. The individual target-table cell and pair-specific orthogonal retest were not inspected; shared source-framework limits are detailed in the notes. This interaction does not establish the partnerโs function in CA8 or an ITPR1-like mechanism. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the curator-supported screen interactions as non-core binding. Reason: CA8โLMNB2 pair (UniProtKB:Q03252) is supported by the preserved GOA assertion and matching UniProt IntAct edge. Retain as non-core with curator deference. The individual target-table cell and pair-specific orthogonal retest were not inspected; shared source-framework limits are detailed in the notes. This interaction does not establish the partnerโs function in CA8 or an ITPR1-like mechanism. |
| GO:0005737 cytoplasm | IEA GO_REF:0000107 | MODIFY | Summary: Refine the broad cytoplasmic compartment to cytosol on independent target evidence. Reason: The original Ensembl orthology-transfer assertion is retained unchanged. The complete cached PMID:30429331 Discussion explicitly describes CA8 as cytosolic, and human CA8 interaction with the cytoplasmic ITPR1 fragment in PMID:19461874 is consistent with that compartment. GO:0005829 names the non-organelle part of the cytoplasm and is part_of GO:0005737. This supports the more precise location without treating channel association as integral ER-membrane insertion or claiming a new endogenous localization assay. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P28651 SUPPORTS TRANSFER Mouse Car8 is the named ortholog source; target cytoplasmic function is independently corroborated. The exact current Ensembl source annotation was not separately re-fetched. ensembl:ENSMUSP00000063511 UNRESOLVED Preserved source identifier; current transcript mapping was not independently reconstructed. Proposed replacements: cytosol |
| GO:0004089 carbonate dehydratase activity | TAS PMID:8977131 Two point mutations convert a catalytically inactive carboni... | REMOVE | Summary: The cited experiment distinguishes inactive wild-type CARP from an engineered active mutant. Reason: The complete PMID:8977131 abstract reports inactive recombinant murine CARP and activity after two engineered substitutions restore the metal-binding environment. The human record has the corresponding loss of a canonical histidine ligand. Thus this paper does not support carbonate dehydratase activity for wild-type human CA8: the TAS has conflated the engineered product with the native ortholog. This conclusion rests on the stated experimental comparison, not its title alone. Supporting Evidence: PMID:8977131 unmodified CARP is catalytically inactive file:human/CA8/CA8-uniprot.txt |
| GO:0019855 calcium channel inhibitor activity | IDA PMID:12611586 Carbonic anhydrase-related protein is a novel binding protei... | NEW | Summary: Retain the prior calcium-channel inhibitor proposal on direct interaction and functional evidence. Reason: CA8 performs the inhibitory work by binding ITPR1 and reducing its IP3 affinity and IP3-evoked calcium release. GO:0019855 is defined as binding to a calcium channel and stopping, preventing or reducing its activity. It retains the demonstrated inhibitory direction that the parent GO:0005246 calcium channel regulator activity does not specify. GO:0044325 transmembrane transporter binding captures association but omits the regulatory consequence; GO:0070679 inositol 1,4,5 trisphosphate binding is not justified because the established target is the receptor, not its ligand. The complete PMID:12611586 abstract describes mouse interaction mapping and affinity reduction; those residue numbers are not transferred to human CA8. PMID:19461874 tests human CA8 and a human receptor fragment. PMID:30429331 couples receptor-defined HeLa calcium imaging with reciprocal V1538M disruption of binding and inhibition. The negative interaction result in PMID:26399641 limits universality across assay contexts and is retained as countervailing evidence, rather than positive support. This reassessment retains the existing authored NEW; it adds no further molecular-function assertion. Supporting Evidence: PMID:12611586 CARP inhibits IP(3) binding to IP(3)R1 by reducing the affinity of the receptor for IP(3). PMID:30429331 V1538M within the CA8-binding site of IP3R1 completely eliminated its interaction with CA8 and CA8-mediated IP3R1 inhibition. |
| GO:0051280 negative regulation of release of sequestered calcium ion into cytosol | IDA PMID:30429331 Aberrant IP(3) receptor activities revealed by comprehensive... | NEW | Summary: Retain the prior process proposal for CA8-mediated inhibition of ER calcium release. Reason: The product is an active negative regulator: CA8 binding modulates ITPR1-mediated release of stored calcium, so CA8 does work in the regulation rather than serving as transported calcium or a passive necessity factor. PMID:30429331 tests suppressed IP3-evoked release and loss of suppression with disease variants. This directly matches GO:0051280 and its regulation-of-release/negative-calcium-transport parents. The local comparator audit finds a GO:0060315 child annotation on the non-catalytic calcium-channel regulator CALM1, whereas BCL2 carries broader calcium-regulation terms; no universal annotation convention or missing-term argument is assumed. No CA8 activity was found in the local GO-CAM index. This prior authored process NEW is complementary to the molecular inhibitor activity, not a redundant same-aspect parent/child proposal; no additional developmental or disease process is proposed. The separate negative CA8โIP3R1 interaction result in PMID:26399641 is discussed as a context limit, not positive evidence for calcium-release inhibition. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: Retain the curator-supported screen interactions as non-core binding. Reason: CA8โCRX pair (UniProtKB:O43186) is supported by the preserved GOA assertion and matching UniProt IntAct edge. Retain as non-core with curator deference. The individual target-table cell and pair-specific orthogonal retest were not inspected; shared source-framework limits are detailed in the notes. This interaction does not establish the partnerโs function in CA8 or an ITPR1-like mechanism. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: Retain the curator-supported screen interactions as non-core binding. Reason: CA8โLNX1 pair (UniProtKB:Q8TBB1) is supported by the preserved GOA assertion and matching UniProt IntAct edge. Retain as non-core with curator deference. The individual target-table cell and pair-specific orthogonal retest were not inspected; shared source-framework limits are detailed in the notes. This interaction does not establish the partnerโs function in CA8 or an ITPR1-like mechanism. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: Retain the curator-supported screen interactions as non-core binding. Reason: CA8โSPDL1 pair (UniProtKB:Q96EA4) is supported by the preserved GOA assertion and matching UniProt IntAct edge. Retain as non-core with curator deference. The individual target-table cell and pair-specific orthogonal retest were not inspected; shared source-framework limits are detailed in the notes. This interaction does not establish the partnerโs function in CA8 or an ITPR1-like mechanism. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: Retain the curator-supported screen interactions as non-core binding. Reason: CA8โHSD17B14 pair (UniProtKB:Q9BPX1) is supported by the preserved GOA assertion and matching UniProt IntAct edge. Retain as non-core with curator deference. The individual target-table cell and pair-specific orthogonal retest were not inspected; shared source-framework limits are detailed in the notes. This interaction does not establish the partnerโs function in CA8 or an ITPR1-like mechanism. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: Retain the curator-supported screen interactions as non-core binding. Reason: CA8โGGA2 pair (UniProtKB:Q9UJY4) is supported by the preserved GOA assertion and matching UniProt IntAct edge. Retain as non-core with curator deference. The individual target-table cell and pair-specific orthogonal retest were not inspected; shared source-framework limits are detailed in the notes. This interaction does not establish the partnerโs function in CA8 or an ITPR1-like mechanism. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: Retain the curator-supported screen interactions as non-core binding. Reason: CA8โMAGED1 pair (UniProtKB:Q9Y5V3) is supported by the preserved GOA assertion and matching UniProt IntAct edge. Retain as non-core with curator deference. The individual target-table cell and pair-specific orthogonal retest were not inspected; shared source-framework limits are detailed in the notes. This interaction does not establish the partnerโs function in CA8 or an ITPR1-like mechanism. |
| GO:0005515 protein binding | IPI PMID:25910212 Widespread macromolecular interaction perturbations in human... | KEEP AS NON CORE | Summary: Retain the curator-supported screen interactions as non-core binding. Reason: CA8โLNX1 pair (UniProtKB:Q8TBB1) is supported by the preserved GOA assertion and matching UniProt IntAct edge. Retain as non-core with curator deference. The individual target-table cell and pair-specific orthogonal retest were not inspected; shared source-framework limits are detailed in the notes. This interaction does not establish the partnerโs function in CA8 or an ITPR1-like mechanism. |
| GO:0005515 protein binding | IPI PMID:25910212 Widespread macromolecular interaction perturbations in human... | KEEP AS NON CORE | Summary: Retain the curator-supported screen interactions as non-core binding. Reason: CA8โSPDL1 pair (UniProtKB:Q96EA4) is supported by the preserved GOA assertion and matching UniProt IntAct edge. Retain as non-core with curator deference. The individual target-table cell and pair-specific orthogonal retest were not inspected; shared source-framework limits are detailed in the notes. This interaction does not establish the partnerโs function in CA8 or an ITPR1-like mechanism. |
| GO:0005515 protein binding | IPI PMID:25910212 Widespread macromolecular interaction perturbations in human... | KEEP AS NON CORE | Summary: Retain the curator-supported screen interactions as non-core binding. Reason: CA8โHSD17B14 pair (UniProtKB:Q9BPX1) is supported by the preserved GOA assertion and matching UniProt IntAct edge. Retain as non-core with curator deference. The individual target-table cell and pair-specific orthogonal retest were not inspected; shared source-framework limits are detailed in the notes. This interaction does not establish the partnerโs function in CA8 or an ITPR1-like mechanism. |
| GO:0005515 protein binding | IPI PMID:25910212 Widespread macromolecular interaction perturbations in human... | KEEP AS NON CORE | Summary: Retain the curator-supported screen interactions as non-core binding. Reason: CA8โRAB34 pair (UniProtKB:Q9BZG1) is supported by the preserved GOA assertion and matching UniProt IntAct edge. Retain as non-core with curator deference. The individual target-table cell and pair-specific orthogonal retest were not inspected; shared source-framework limits are detailed in the notes. This interaction does not establish the partnerโs function in CA8 or an ITPR1-like mechanism. |
| GO:0005515 protein binding | IPI PMID:25910212 Widespread macromolecular interaction perturbations in human... | KEEP AS NON CORE | Summary: Retain the curator-supported screen interactions as non-core binding. Reason: CA8โINTS7 pair (UniProtKB:Q9NVH2) is supported by the preserved GOA assertion and matching UniProt IntAct edge. Retain as non-core with curator deference. The individual target-table cell and pair-specific orthogonal retest were not inspected; shared source-framework limits are detailed in the notes. This interaction does not establish the partnerโs function in CA8 or an ITPR1-like mechanism. |
| GO:0005515 protein binding | IPI PMID:25910212 Widespread macromolecular interaction perturbations in human... | KEEP AS NON CORE | Summary: Retain the curator-supported screen interactions as non-core binding. Reason: CA8โGGA2 pair (UniProtKB:Q9UJY4) is supported by the preserved GOA assertion and matching UniProt IntAct edge. Retain as non-core with curator deference. The individual target-table cell and pair-specific orthogonal retest were not inspected; shared source-framework limits are detailed in the notes. This interaction does not establish the partnerโs function in CA8 or an ITPR1-like mechanism. |
| GO:0005515 protein binding | IPI PMID:25910212 Widespread macromolecular interaction perturbations in human... | KEEP AS NON CORE | Summary: Retain the curator-supported screen interactions as non-core binding. Reason: CA8โMAGED1 pair (UniProtKB:Q9Y5V3) is supported by the preserved GOA assertion and matching UniProt IntAct edge. Retain as non-core with curator deference. The individual target-table cell and pair-specific orthogonal retest were not inspected; shared source-framework limits are detailed in the notes. This interaction does not establish the partnerโs function in CA8 or an ITPR1-like mechanism. |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | KEEP AS NON CORE | Summary: Retain the curator-supported screen interactions as non-core binding. Reason: CA8โHSD17B14 pair (UniProtKB:Q9BPX1) is supported by the preserved GOA assertion and matching UniProt IntAct edge. Retain as non-core with curator deference. The individual target-table cell and pair-specific orthogonal retest were not inspected; shared source-framework limits are detailed in the notes. This interaction does not establish the partnerโs function in CA8 or an ITPR1-like mechanism. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the curator-supported screen interactions as non-core binding. Reason: CA8โHSD17B14 pair (UniProtKB:Q9BPX1) is supported by the preserved GOA assertion and matching UniProt IntAct edge. Retain as non-core with curator deference. The individual target-table cell and pair-specific orthogonal retest were not inspected; shared source-framework limits are detailed in the notes. This interaction does not establish the partnerโs function in CA8 or an ITPR1-like mechanism. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the curator-supported screen interactions as non-core binding. Reason: CA8โKLHL8 pair (UniProtKB:Q9P2G9-2) is supported by the preserved GOA assertion and matching UniProt IntAct edge. Retain as non-core with curator deference. The individual target-table cell and pair-specific orthogonal retest were not inspected; shared source-framework limits are detailed in the notes. This interaction does not establish the partnerโs function in CA8 or an ITPR1-like mechanism. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the curator-supported screen interactions as non-core binding. Reason: CA8โMAGED1 pair (UniProtKB:Q9Y5V3) is supported by the preserved GOA assertion and matching UniProt IntAct edge. Retain as non-core with curator deference. The individual target-table cell and pair-specific orthogonal retest were not inspected; shared source-framework limits are detailed in the notes. This interaction does not establish the partnerโs function in CA8 or an ITPR1-like mechanism. |
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Download this section (compressed HTML)Q: How do the negative CA8โIP3R1 binding result in the PKCฮณ/Purkinje-culture system and positive recombinant/HeLa assays depend on construct, expression level and assay context? Does part of the dendritic phenotype reflect an ITPR1-independent mechanism?
Q: Which CA8 residues directly contact ITPR1, and how does binding alter ligand sensitivity or gating? Current interface predictions and broad deletion mapping do not establish that the former catalytic cavity is the contact surface.
Q: Would a curated NOT carbonate-dehydratase assertion and a refined InterPro mapping prevent repeated transfer of catalytic activity to native CA8, while retaining the distinction from engineered active mutants?
Q: Which physiological settings support the screen-derived CA8 partner interactions, and can targeted experiments assign a molecular activity more specific than binding without assuming they share the ITPR1 mechanism?
Q: Why is ITPR1 absent from the preserved CA8 generic-binding GOA rows despite targeted interaction studies in PMID:12611586, PMID:19461874 and PMID:30429331? Does this reflect curation scope or a missing targeted assertion, and is the existing calcium-channel inhibitor proposal the more informative representation? No additional generic-binding NEW is inferred from absence.
Q: Do CA10 and CA11 carry comparable InterPro-derived carbonate-dehydratase or zinc-binding assertions, and would their own sequence and biochemical evidence justify analogous mapping corrections? Their interaction mechanisms must be checked separately rather than assumed to use the CA8 interface.
Q: Would an ontology term for allosteric inhibition of an intracellular IP3-gated calcium-release channel add useful precision beyond GO:0019855, or is the current term adequate? Any proposed new term should be justified against current definitions and intended scope.
Q: Does wild-type CA8 catalyze a reaction other than CO2 hydration? The demonstrated loss of canonical carbonic-anhydrase activity does not establish absence of every possible chemical activity.
Experiment: Compare purified wild-type human CA8 with stable separation-of-function variants in an ITPR1 binding and calcium-release system, measuring concentration dependence and channel response separately from protein stability.
Experiment: Reproduce the positive biochemical/HeLa and negative Purkinje-culture interaction assays with matched tagged and untagged constructs, expression controls and orthogonal interaction measurements.
Experiment: Determine a CA8โITPR1 regulatory complex structure, using cryo-EM or another method suited to the assembled complex, and test interface-specific variants that preserve folding. This would distinguish a predicted former-cavity interface from experimentally resolved contacts and connect binding to changes in IP3 sensitivity.
Experiment: Screen purified wild-type human CA8 for residual esterase and selected small-molecule hydrolysis/hydration activities, with active CA2, buffer and protein-purity controls. Include sequence-verified engineered metal-site restoration variants as comparators without assuming that one human substitution reproduces the historical murine double-mutant result.
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