id: A0A5F5PZM5 gene_symbol: CACNB3 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9796 label: Equus caballus description: CACNB3 encodes the beta3 auxiliary subunit of high voltage-activated calcium channels. It is a cytoplasmic protein built from an SH3 domain, a HOOK region and a catalytically inactive guanylate-kinase-like domain; the guanylate-kinase-like domain binds the alpha-interaction domain in the intracellular I-II loop of the pore-forming alpha1 subunit. By binding alpha1, beta3 increases channel surface expression and peak current and shifts the voltage dependence of activation and inactivation of L-type (Cav1) and N-type (Cav2.2) channels, so it controls calcium influx in neurons, smooth muscle and other excitable cells. The horse entry A0A5F5PZM5 is an alternative first-exon model of the gene whose conserved core is almost identical to human beta3. existing_annotations: - term: id: GO:0005245 label: voltage-gated calcium channel activity evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: enables supporting_entities: - UniProtKB:P54284 - ensembl:ENSP00000301050 - InterPro:IPR000584 - InterPro:IPR008079 review: summary: Combined IEA (InterPro VDCC beta signatures) assigns pore activity to a subunit that has no pore. action: MODIFY reason: CACNB3 is the cytoplasmic auxiliary beta subunit; the calcium-conducting pore is formed by the alpha1 subunit. The horse protein is the beta3 ortholog (99.78% core identity to human CACNB3 versus 63-74% to the other beta paralogs), and human beta3 modulates channel current amplitude and gating when coexpressed with alpha1. The correct molecular function is calcium channel regulator activity. supported_by: - &id002 reference_id: file:human/CACNB3/CACNB3-uniprot.txt record_section: ["CC:FUNCTION"] supporting_text: 'CC -!- FUNCTION: Regulatory subunit of the voltage-gated calcium channel that CC gives rise to L-type calcium currents (PubMed:8119293).' - &id005 reference_id: PMID:8119293 supporting_text: 'The cloned H beta 3 subunit was further expressed in Xenopus oocytes to demonstrate its ability to modulate VDCC activity.' - &id001 reference_id: file:HORSE/CACNB3/CACNB3-bioinformatics/RESULTS-rereview.md supporting_text: Over the shared core, A0A5F5PZM5 is 99.78% identical to human CACNB3 (P54284; 464/465 paired residues), against 63.36% to CACNB1 (Q02641), 65.09% to CACNB2 (Q08289) and 74.14% to CACNB4 (O00305). proposed_replacement_terms: - &id007 id: GO:0005246 label: calcium channel regulator activity - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in supporting_entities: - UniProtKB-SubCell:SL-0086 review: summary: Beta3 is a cytoplasmic subunit binding the intracellular alpha-interaction domain of alpha1. action: ACCEPT reason: UniProt SubCell mapping to cytoplasm. Human beta3 is a soluble cytoplasmic protein that docks on the intracellular I-II loop of alpha1, as resolved in the human Cav2.2 cryo-EM structure; the horse core is near-identical, so the location transfers. supported_by: - reference_id: file:human/CACNB3/CACNB3-uniprot.txt record_section: ["CC:SUBCELLULAR LOCATION"] supporting_text: 'CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:34234349}.' - &id003 reference_id: PMID:34234349 supporting_text: "cryo-electron microscopy structures of human Cav2.2 (comprising the core α1 and \nthe ancillary\ \ α2δ-1 and β3 subunits)" - *id001 - term: id: GO:0005891 label: voltage-gated calcium channel complex evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: part_of supporting_entities: - MGI:MGI:102522 - MGI:MGI:103301 - MGI:MGI:103307 - MGI:MGI:894644 - PANTHER:PTN000930213 - RGD:2248 - RGD:67385 - RGD:68382 - UniProtKB:O00305 - UniProtKB:P54284 - UniProtKB:Q02641 - UniProtKB:Q08289 - UniProtKB:Q9MZL5 - ZFIN:ZDB-GENE-040718-399 review: summary: Family-wide PAINT assertion at PTN000930213; human beta3 is a structurally resolved subunit of Cav channel complexes. action: ACCEPT reason: The PAINT node covers all calcium-channel beta subunits and is seeded by experimental annotations of many members, including human CACNB3. Horse A0A5F5PZM5 is the beta3 ortholog and lies inside this clade. Human beta3 is a subunit of both Cav1 (L-type) and Cav2.2 (N-type) complexes. supported_by: - *id002 - *id003 - &id004 reference_id: PMID:11160515 supporting_text: 'co-expressed with alpha(2)delta-1 and beta(3a)' - *id001 - term: id: GO:0005891 label: voltage-gated calcium channel complex evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: part_of supporting_entities: - ARBA:ARBA00088150 - UniProtKB:P54284 - ensembl:ENSP00000301050 - UniProtKB:P54285 - ensembl:ENSMUSP00000155514 - InterPro:IPR000584 - InterPro:IPR008079 review: summary: Consistent with the IBA row; beta3 is a subunit of voltage-gated calcium channel complexes. action: ACCEPT reason: Same claim as the IBA row. Human beta3 is resolved as an ancillary subunit in the Cav2.2 complex structure and assembles with L-type alpha1D in functional channels; the horse ortholog has an identical core. supported_by: - *id003 - *id004 - *id001 - term: id: GO:0006816 label: calcium ion transport evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in supporting_entities: - FB:FBgn0287724 - MGI:MGI:102522 - MGI:MGI:103301 - PANTHER:PTN000930213 - RGD:2248 - RGD:68385 - UniProtKB:O00305 - UniProtKB:P54284 - UniProtKB:Q08289 review: summary: True but general; beta3 acts on transmembrane calcium influx through the channel, already captured by GO:0070588. action: MODIFY reason: Beta3 contributes to calcium transport only as a regulatory subunit of the plasma-membrane channel complex, i.e. to calcium ion transmembrane transport (GO:0070588), a descendant that horse CACNB3 already carries. The PAINT inference itself is sound for this clade. supported_by: - *id002 - *id005 - *id001 proposed_replacement_terms: - &id006 id: GO:0070588 label: calcium ion transmembrane transport propagation_review: root_cause: TERM_SCOPING_PROBLEM failure_modes: - GRANULARITY_MISMATCH source_entities: - source_id: PANTHER:PTN000930213 comment: Family-wide calcium-channel beta node; the target horse beta3 lies inside it. Placement is sound; the parent process is true but less specific than transmembrane transport. source_status: SUPPORTS_TRANSFER - source_id: UniProtKB:P54284 comment: Human CACNB3, the ortholog of the target, is one of the experimental descendants grounding the node. source_status: SUPPORTS_TRANSFER - term: id: GO:0006816 label: calcium ion transport evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in supporting_entities: - UniProtKB:P54284 - ensembl:ENSP00000301050 review: summary: Ensembl Compara projection of the human calcium ion transport annotation; refine to transmembrane transport. action: MODIFY reason: Same claim as the IBA row; the specific supported process is calcium ion transmembrane transport (GO:0070588), already on this gene. supported_by: - *id002 - *id005 - *id001 proposed_replacement_terms: - *id006 - term: id: GO:0008331 label: high voltage-gated calcium channel activity evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables supporting_entities: - MGI:MGI:102522 - PANTHER:PTN000930213 review: summary: PAINT propagated pore activity of the assembled channel to the beta subunit; the beta subunit regulates rather than conducts. action: MODIFY reason: The PTN000930213 MF assertion is seeded by a single mouse beta subunit and states high voltage-gated calcium channel activity without a contributes_to qualifier. Beta subunits lack transmembrane segments and a pore; their activity is regulation of the HVA alpha1 subunit (current amplitude, voltage dependence, surface expression). The phylogenetic placement of the horse protein in the clade is not in question, only the term. supported_by: - *id002 - *id005 - *id001 proposed_replacement_terms: - *id007 propagation_review: root_cause: TERM_SCOPING_PROBLEM failure_modes: - ROLE_CONFLATION source_entities: - source_id: PANTHER:PTN000930213 comment: Node placement covers all beta subunits including the target; the asserted MF names the activity of the assembled channel pore rather than the beta-subunit regulatory activity. source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET - source_id: MGI:MGI:102522 comment: Single mouse beta-subunit seed; a channel-activity annotation on a beta subunit reflects coexpression with alpha1, which fits contributes_to or regulator activity. source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET - term: id: GO:0016020 label: membrane evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in supporting_entities: - UniProtKB:P54284 - ensembl:ENSP00000301050 review: summary: Projected from a human membrane-proteomics observation; beta3 is peripheral on the cytoplasmic face of membrane channel complexes. action: KEEP_AS_NON_CORE reason: Membrane association arises from binding to the membrane-embedded alpha1 subunit; beta3 has no transmembrane segment or known lipid anchor. The term is true at the level of resolution the source supports but is not the core location (which is the channel complex and cytoplasm). supported_by: - *id003 - *id001 - term: id: GO:0070588 label: calcium ion transmembrane transport evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: involved_in supporting_entities: - UniProtKB:P54284 - ensembl:ENSP00000301050 - InterPro:IPR000584 - InterPro:IPR008079 review: summary: Beta3 participates in transmembrane calcium influx as a regulatory subunit of the channel complex. action: ACCEPT reason: Coexpression of human beta3 modulates voltage-dependent calcium channel currents, and beta3 is a structural subunit of the channel complex. Participation in calcium ion transmembrane transport as a channel-complex subunit is appropriate; horse core identity supports transfer. supported_by: - *id002 - *id005 - *id001 - term: id: GO:1990454 label: L-type voltage-gated calcium channel complex evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: part_of supporting_entities: - UniProtKB:P54284 - ensembl:ENSP00000301050 review: summary: Beta3 assembles with L-type alpha1 subunits (Cav1.2, Cav1.3). action: ACCEPT reason: Human beta3a coexpressed with alpha1D and alpha2delta-1 forms functional L-type channels, and UniProt records beta3 in a CACNA1C complex. Beta3 is not L-type-exclusive (it is also in the Cav2.2 structure), but L-type membership is supported. supported_by: - *id002 - *id004 - *id001 references: - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000044 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt findings: [] - id: GO_REF:0000107 title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara findings: [] - id: GO_REF:0000120 title: Combined Automated Annotation using Multiple IEA Methods findings: [] - id: file:human/CACNB3/CACNB3-uniprot.txt title: UniProt record for human CACNB3 findings: [] - id: file:HORSE/CACNB3/CACNB3-bioinformatics/RESULTS.md title: 'CACNB3: horse–human sequence comparison' findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Original pairwise horse-human comparison. Its identity figures are correct but it does not test paralogs or explain the 49-residue N-terminal difference; the re-review cites RESULTS-rereview.md instead. Kept for provenance. - id: PMID:8119293 title: Cloning, chromosomal location and functional expression of the human voltage-dependent calcium-channel beta 3 subunit. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Primary cloning and Xenopus oocyte functional expression of human beta3 (abstract only cached). - id: file:HORSE/CACNB3/CACNB3-bioinformatics/RESULTS-rereview.md title: 'CACNB3 (horse A0A5F5PZM5): paralog and gene-model re-review' findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Generated by compare_paralogs_rereview.py from live UniProt sequences; establishes beta3 paralog placement and the alternative first-exon gene model. - id: PMID:11160515 title: Biophysical properties, pharmacology, and modulation of human, neuronal L-type (alpha(1D), Ca(V)1.3) voltage-dependent calcium currents. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Abstract states alpha1D was co-expressed with alpha2delta-1 and beta3a to form L-type currents; supports beta3 in L-type complexes. - id: PMID:34234349 title: Structure of human Ca(v)2.2 channel blocked by the painkiller ziconotide. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Cryo-EM structure of human Cav2.2 containing beta3 as ancillary subunit (abstract). core_functions: - description: Auxiliary beta3 subunit that binds the pore-forming alpha1 subunit of high voltage-activated calcium channels and regulates their surface expression, current amplitude and voltage-dependent gating. molecular_function: *id007 directly_involved_in: - *id006 locations: - id: GO:0005737 label: cytoplasm in_complex: id: GO:0005891 label: voltage-gated calcium channel complex supported_by: - *id002 - *id005 - *id003 - *id001 suggested_questions: - question: Is the 49-residue alternative first exon of horse model A0A5F5PZM5 supported by transcript evidence, and does it alter beta3 modulation of inactivation as alternative N-termini do for other beta subunits?