CIB2 is a small intracellular EF-hand protein that binds calcium and magnesium and engages several protein partners. In sensory hair cells it associates with cytoplasmic regions of TMC channels and regulates the mechanotransduction apparatus at stereocilia. CIB2 also binds integrin cytoplasmic tails, and its C-terminal peptide recognizes PDZ domains. In a distinct signaling context, CIB2 associates with RHEB and Raptor and restrains mTORC1 signaling; loss in the retinal pigment epithelium impairs phagolysosomal processing and can secondarily compromise photoreceptor function. Calcium-dependent conformational changes influence partner interactions, while the precise connection between metal occupancy and channel gating remains unresolved. Alternative products differ in their N-terminal regions or C-terminal tail.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000287 magnesium ion binding | IBA GO_REF:0000033 | ACCEPT | Summary: Retain magnesium binding by the EF-hand protein. Reason: The authentic original human CIB2 study explicitly reports purified-protein Mg binding. The later human CIB2–TMC1 domain structure assigns Mg to EF3 and EF4 under its crystallization conditions. This supports the molecular capability without assuming physiological saturation, a fixed metal preference in every compartment, or equivalent behavior of all four products. The curated PAINT assertion is corroborated by target evidence; historical ancestral placement was not reconstructed. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002507469 SUPPORTS TRANSFER Human CIB2 Mg binding and the Mg-bound human complex structure corroborate this metal-binding transfer. The authenticated curated node is retained, but its historical IBD placement, tree and MSA were not reconstructed. Current donor records are contextual, not a substitute reconstruction. Supporting Evidence: GO_REF:0000033 file:human/CIB2/CIB2-source-evidence.json |
| GO:0000287 magnesium ion binding | IDA PMID:22779914 Biophysical and structural studies of the human calcium- and... | ACCEPT | Summary: Retain magnesium binding by the EF-hand protein. Reason: The authentic original human CIB2 study explicitly reports purified-protein Mg binding. The later human CIB2–TMC1 domain structure assigns Mg to EF3 and EF4 under its crystallization conditions. This supports the molecular capability without assuming physiological saturation, a fixed metal preference in every compartment, or equivalent behavior of all four products. The original full body remains inaccessible, so no uninspected binding constants are quoted; the positive abstract and independent human structure agree. |
| GO:0000287 magnesium ion binding | IEA GO_REF:0000117 | ACCEPT | Summary: Retain magnesium binding by the EF-hand protein. Reason: The authentic original human CIB2 study explicitly reports purified-protein Mg binding. The later human CIB2–TMC1 domain structure assigns Mg to EF3 and EF4 under its crystallization conditions. This supports the molecular capability without assuming physiological saturation, a fixed metal preference in every compartment, or equivalent behavior of all four products. The exact ARBA source is retained; independent human biochemistry corroborates its target-level conclusion rather than reconstructing the historical rule execution. Supporting Evidence: GO_REF:0000117 file:human/CIB2/CIB2-source-evidence.json |
| GO:0001750 photoreceptor outer segment | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Retain the ortholog-supported photoreceptor outer segment pool. Reason: The authenticated donor Q9Z309 is mouse Cib2; its current source is IDA/PMID:23023331. The actual study immunolocalizes endogenous CIB2 in mouse retinal outer segments, alongside other retinal compartments. Preserve this orthology-based location, without relabeling it as direct human microscopy. Later RPE-specific loss affects photoreceptor function, whereas rod-specific loss did not reproduce that phenotype; localization alone does not establish an autonomous photoreceptor maintenance mechanism. Supporting Evidence: GO_REF:0000120 file:human/CIB2/CIB2-source-evidence.json |
| GO:0001750 photoreceptor outer segment | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Retain the ortholog-supported photoreceptor outer segment pool. Reason: The authenticated donor Q9Z309 is mouse Cib2; its current source is IDA/PMID:23023331. The actual study immunolocalizes endogenous CIB2 in mouse retinal outer segments, alongside other retinal compartments. Preserve this orthology-based location, without relabeling it as direct human microscopy. Later RPE-specific loss affects photoreceptor function, whereas rod-specific loss did not reproduce that phenotype; localization alone does not establish an autonomous photoreceptor maintenance mechanism. Supporting Evidence: GO_REF:0000024 file:human/CIB2/CIB2-source-evidence.json |
| GO:0001917 photoreceptor inner segment | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Retain the ortholog-supported photoreceptor inner segment pool. Reason: The authenticated donor Q9Z309 is mouse Cib2; its current source is IDA/PMID:23023331. The actual study immunolocalizes endogenous CIB2 in mouse retinal inner segments, alongside other retinal compartments. Preserve this orthology-based location, without relabeling it as direct human microscopy. Later RPE-specific loss affects photoreceptor function, whereas rod-specific loss did not reproduce that phenotype; localization alone does not establish an autonomous photoreceptor maintenance mechanism. Supporting Evidence: GO_REF:0000120 file:human/CIB2/CIB2-source-evidence.json |
| GO:0001917 photoreceptor inner segment | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Retain the ortholog-supported photoreceptor inner segment pool. Reason: The authenticated donor Q9Z309 is mouse Cib2; its current source is IDA/PMID:23023331. The actual study immunolocalizes endogenous CIB2 in mouse retinal inner segments, alongside other retinal compartments. Preserve this orthology-based location, without relabeling it as direct human microscopy. Later RPE-specific loss affects photoreceptor function, whereas rod-specific loss did not reproduce that phenotype; localization alone does not establish an autonomous photoreceptor maintenance mechanism. Supporting Evidence: GO_REF:0000024 file:human/CIB2/CIB2-source-evidence.json |
| GO:0005178 integrin binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Retain integrin-tail binding as a distinct contextual interaction. Reason: Mouse donor Q9Z309 has an actual IPI/PMID:18611855 assertion: recombinant mouse Cib2 binds the alpha7B cytoplasmic peptide and associates with alpha7B–beta1D from muscle lysate. Independently, PMID:22779914 explicitly reports purified human CIB2 binding to alphaIIb and alpha7B fragments. This supports binding, without converting the proposed integrin-activation model into demonstrated activation. Supporting Evidence: GO_REF:0000107 file:human/CIB2/CIB2-source-evidence.json |
| GO:0005509 calcium ion binding | IBA GO_REF:0000033 | ACCEPT | Summary: Retain calcium binding and its conformational consequences. Reason: Purified human CIB2 binds Ca in PMID:22779914; the later human TMC1-domain assays show calcium-dependent changes in partner affinity. Mouse Cib2 also has a direct Ca-overlay result in PMID:18611855. Calcium binding is a molecular property, not proof that CIB2 universally controls adaptation or that all alternative products have identical affinity. The actual PAINT source is retained with independent target grounding; the historical family tree and IBD placement remain uninspected. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002507469 SUPPORTS TRANSFER Direct human CIB2 Ca binding and independent mouse binding support this transfer. The authenticated curated node is retained, but its historical IBD placement, tree and MSA were not reconstructed. Current donor records are contextual, not a substitute reconstruction. Supporting Evidence: GO_REF:0000033 file:human/CIB2/CIB2-source-evidence.json |
| GO:0005509 calcium ion binding | IDA PMID:22779914 Biophysical and structural studies of the human calcium- and... | ACCEPT | Summary: Retain calcium binding and its conformational consequences. Reason: Purified human CIB2 binds Ca in PMID:22779914; the later human TMC1-domain assays show calcium-dependent changes in partner affinity. Mouse Cib2 also has a direct Ca-overlay result in PMID:18611855. Calcium binding is a molecular property, not proof that CIB2 universally controls adaptation or that all alternative products have identical affinity. The original abstract is explicitly positive for CIB2; its inaccessible full body is not replaced by invented assay details. |
| GO:0005509 calcium ion binding | IEA GO_REF:0000120 | ACCEPT | Summary: Retain calcium binding and its conformational consequences. Reason: Purified human CIB2 binds Ca in PMID:22779914; the later human TMC1-domain assays show calcium-dependent changes in partner affinity. Mouse Cib2 also has a direct Ca-overlay result in PMID:18611855. Calcium binding is a molecular property, not proof that CIB2 universally controls adaptation or that all alternative products have identical affinity. The exact mouse and EF-hand source fields are preserved; the conclusion has direct human support beyond a domain-name inference. Supporting Evidence: GO_REF:0000120 file:human/CIB2/CIB2-source-evidence.json |
| GO:0005515 protein binding | IPI PMID:22779914 Biophysical and structural studies of the human calcium- and... | MODIFY | Summary: Specify integrin binding. Reason: The source abstract explicitly reports purified human CIB2 interaction with the integrin alphaIIb cytoplasmic region. The exact partner identity agrees with the original source object. Integrin binding is a more informative description of this interaction; full-length receptor activation, native cellular encounter and binding constants are not inferred from the inaccessible original body. Proposed replacements: integrin binding |
| GO:0005515 protein binding | IPI PMID:22779914 Biophysical and structural studies of the human calcium- and... | MODIFY | Summary: Specify integrin binding. Reason: The source abstract explicitly reports purified human CIB2 interaction with the integrin alpha7B cytoplasmic region. The exact partner identity agrees with the original source object. Integrin binding is a more informative description of this interaction; full-length receptor activation, native cellular encounter and binding constants are not inferred from the inaccessible original body. Proposed replacements: integrin binding |
| GO:0005515 protein binding | IPI PMID:23023331 Alterations of the CIB2 calcium- and integrin-binding protei... | MODIFY | Summary: Specify binding to myosin VIIa. Reason: PMID:23023331 reports tagged CIB2–myosin VIIa association in its co-immunoprecipitation experiments. MYO7A/Q13402 is an authenticated unconventional myosin, so the partner-class term describes the demonstrated interaction. This does not assign motor activity to CIB2 or prove that MYO7A recruits it to stereocilia; the paper found no CIB2 mislocalization in the tested Myo7a mutant. Proposed replacements: myosin binding |
| GO:0005515 protein binding | IPI PMID:23023331 Alterations of the CIB2 calcium- and integrin-binding protei... | KEEP AS NON CORE | Summary: Retain the whirlin association without inventing its interface. Reason: The actual PMID:23023331 co-immunoprecipitation result supports CIB2 association with whirlin. The Methods include human CIB2 and mouse whirlin constructs; the original human partner object is preserved without pretending every species combination was tested. This result does not map a whirlin PDZ domain interface or establish that CIB2 is a scaffold, adaptor or localization factor. Supported generic binding is retained as non-core under project policy. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: Retain the PARD3B affinity-purification association at its measured scope. Reason: The exact PMID:33961781 record detects PARD3B association by anti-tag affinity purification in HEK293T cells; it does not map the contact to a PDZ domain or establish a purified binary interaction. Retain this positive association as non-core. The independent PMID:36115835 holdup experiment directly tests the CIB2 178–187 peptide against the PARD3B 184–299 PDZ fragment and retains its own PDZ-domain refinement. This source-specific allocation does not negate that interface or imply that corroborating references and repeated assertions are inherently invalid. Whirlin likewise retains its positive co-IP, but no independent mapped whirlin interface was established. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Specify the directly tested PDZ-domain interaction. Reason: PMID:36115835 directly measures holdup binding of the biotinylated canonical CIB2 178–187 peptide to His6–MBP A4D2P6 (GRID2IP) PDZ fragments 272-370, 1-87. PDZ domain binding describes this tested interface; the alternative O75838-2 tail differs, and full-length interactions of individual products were not established. Proposed replacements: PDZ domain binding |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Specify the directly tested PDZ-domain interaction. Reason: PMID:36115835 directly measures holdup binding of the biotinylated canonical CIB2 178–187 peptide to His6–MBP O75970 (MPDZ) PDZ fragments 1624-1716, 1858-1949, 688-793. PDZ domain binding describes this tested interface; the alternative O75838-2 tail differs, and full-length interactions of individual products were not established. Proposed replacements: PDZ domain binding |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Specify the directly tested PDZ-domain interaction. Reason: PMID:36115835 directly measures holdup binding of the biotinylated canonical CIB2 178–187 peptide to His6–MBP P78352 (DLG4) PDZ fragments 62-152, 155-249. PDZ domain binding describes this tested interface; the alternative O75838-2 tail differs, and full-length interactions of individual products were not established. Proposed replacements: PDZ domain binding |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Specify the directly tested PDZ-domain interaction. Reason: PMID:36115835 directly measures holdup binding of the biotinylated canonical CIB2 178–187 peptide to His6–MBP Q02410 (APBA1) PDZ fragments 655-741, 742-822. PDZ domain binding describes this tested interface; the alternative O75838-2 tail differs, and full-length interactions of individual products were not established. Proposed replacements: PDZ domain binding |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Specify the directly tested PDZ-domain interaction. Reason: PMID:36115835 directly measures holdup binding of the biotinylated canonical CIB2 178–187 peptide to His6–MBP Q07157 (TJP1) PDZ fragments 415-516, 184-264. PDZ domain binding describes this tested interface; the alternative O75838-2 tail differs, and full-length interactions of individual products were not established. Proposed replacements: PDZ domain binding |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Specify the directly tested PDZ-domain interaction. Reason: PMID:36115835 directly measures holdup binding of the biotinylated canonical CIB2 178–187 peptide to His6–MBP Q12959 (DLG1) PDZ fragments 314-412, 457-571, 221-314. PDZ domain binding describes this tested interface; the alternative O75838-2 tail differs, and full-length interactions of individual products were not established. Proposed replacements: PDZ domain binding |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Specify the directly tested PDZ-domain interaction. Reason: PMID:36115835 directly measures holdup binding of the biotinylated canonical CIB2 178–187 peptide to His6–MBP Q14005 (IL16) PDZ fragments 210-306, 1203-1332, 1106-1201. PDZ domain binding describes this tested interface; the alternative O75838-2 tail differs, and full-length interactions of individual products were not established. Proposed replacements: PDZ domain binding |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Specify the directly tested PDZ-domain interaction. Reason: PMID:36115835 directly measures holdup binding of the biotinylated canonical CIB2 178–187 peptide to His6–MBP Q14160 (SCRIB) PDZ fragments 718-814, 858-949. PDZ domain binding describes this tested interface; the alternative O75838-2 tail differs, and full-length interactions of individual products were not established. Proposed replacements: PDZ domain binding |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Specify the directly tested PDZ-domain interaction. Reason: PMID:36115835 directly measures holdup binding of the biotinylated canonical CIB2 178–187 peptide to His6–MBP Q15700 (DLG2) PDZ fragments 189-283, 418-513. PDZ domain binding describes this tested interface; the alternative O75838-2 tail differs, and full-length interactions of individual products were not established. Proposed replacements: PDZ domain binding |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Specify the directly tested PDZ-domain interaction. Reason: PMID:36115835 directly measures holdup binding of the biotinylated canonical CIB2 178–187 peptide to His6–MBP Q5T2W1 (PDZK1) PDZ fragments 238-329, 2-107. PDZ domain binding describes this tested interface; the alternative O75838-2 tail differs, and full-length interactions of individual products were not established. Proposed replacements: PDZ domain binding |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Specify the directly tested PDZ-domain interaction. Reason: PMID:36115835 directly measures holdup binding of the biotinylated canonical CIB2 178–187 peptide to His6–MBP Q68DX3 (FRMPD2) PDZ fragments 1073-1166, 770-861, 944-1038. PDZ domain binding describes this tested interface; the alternative O75838-2 tail differs, and full-length interactions of individual products were not established. Proposed replacements: PDZ domain binding |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Specify the directly tested PDZ-domain interaction. Reason: PMID:36115835 directly measures holdup binding of the biotinylated canonical CIB2 178–187 peptide to His6–MBP Q86UL8 (MAGI2) PDZ fragments 772-865, 1141-1229, 915-1017, 600-682, 410-522. PDZ domain binding describes this tested interface; the alternative O75838-2 tail differs, and full-length interactions of individual products were not established. Proposed replacements: PDZ domain binding |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Specify the directly tested PDZ-domain interaction. Reason: PMID:36115835 directly measures holdup binding of the biotinylated canonical CIB2 178–187 peptide to His6–MBP Q86UT5 (NHERF4) PDZ fragments 220-308, 464-550. PDZ domain binding describes this tested interface; the alternative O75838-2 tail differs, and full-length interactions of individual products were not established. Proposed replacements: PDZ domain binding |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Specify the directly tested PDZ-domain interaction. Reason: PMID:36115835 directly measures holdup binding of the biotinylated canonical CIB2 178–187 peptide to His6–MBP Q8NI35 (PATJ) PDZ fragments 113-229, 359-469, 673-780, 1673-1763, 1058-1167, 1425-1530, 547-651, 238-335. PDZ domain binding describes this tested interface; the alternative O75838-2 tail differs, and full-length interactions of individual products were not established. Proposed replacements: PDZ domain binding |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Specify the directly tested PDZ-domain interaction. Reason: PMID:36115835 directly measures holdup binding of the biotinylated canonical CIB2 178–187 peptide to His6–MBP Q8TBB1 (LNX1) PDZ fragments 500-597, 261-371, 371-470. PDZ domain binding describes this tested interface; the alternative O75838-2 tail differs, and full-length interactions of individual products were not established. Proposed replacements: PDZ domain binding |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Specify the directly tested PDZ-domain interaction. Reason: PMID:36115835 directly measures holdup binding of the biotinylated canonical CIB2 178–187 peptide to His6–MBP Q8TEW8 (PARD3B) PDZ fragments 184-299. PDZ domain binding describes this tested interface; the alternative O75838-2 tail differs, and full-length interactions of individual products were not established. Proposed replacements: PDZ domain binding |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Specify the directly tested PDZ-domain interaction. Reason: PMID:36115835 directly measures holdup binding of the biotinylated canonical CIB2 178–187 peptide to His6–MBP Q92796 (DLG3) PDZ fragments 222-314, 124-219, 381-476. PDZ domain binding describes this tested interface; the alternative O75838-2 tail differs, and full-length interactions of individual products were not established. Proposed replacements: PDZ domain binding |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Specify the directly tested PDZ-domain interaction. Reason: PMID:36115835 directly measures holdup binding of the biotinylated canonical CIB2 178–187 peptide to His6–MBP Q96QZ7 (MAGI1) PDZ fragments 456-580, 1-106. PDZ domain binding describes this tested interface; the alternative O75838-2 tail differs, and full-length interactions of individual products were not established. Proposed replacements: PDZ domain binding |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Specify the directly tested PDZ-domain interaction. Reason: PMID:36115835 directly measures holdup binding of the biotinylated canonical CIB2 178–187 peptide to His6–MBP Q99767 (APBA2) PDZ fragments 565-653, 655-735. PDZ domain binding describes this tested interface; the alternative O75838-2 tail differs, and full-length interactions of individual products were not established. Proposed replacements: PDZ domain binding |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Specify the directly tested PDZ-domain interaction. Reason: PMID:36115835 directly measures holdup binding of the biotinylated canonical CIB2 178–187 peptide to His6–MBP Q9C0E4 (GRIP2) PDZ fragments 649-740, 934-1023, 446-548, 238-339, 544-642. PDZ domain binding describes this tested interface; the alternative O75838-2 tail differs, and full-length interactions of individual products were not established. Proposed replacements: PDZ domain binding |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Specify the directly tested PDZ-domain interaction. Reason: PMID:36115835 directly measures holdup binding of the biotinylated canonical CIB2 178–187 peptide to His6–MBP Q9Y3R0 (GRIP1) PDZ fragments 242-344, 996-1086, 563-659, 145-239. PDZ domain binding describes this tested interface; the alternative O75838-2 tail differs, and full-length interactions of individual products were not established. Proposed replacements: PDZ domain binding |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: Retain the cytoplasmic site of CIB2 interactions. Reason: CIB2 is a soluble intracellular protein that binds the cytoplasmic regions of TMC channels and participates in cellular protein complexes. Endogenous mouse tissue staining and human-protein cellular assays support this broad compartment. Preserve the curated PAINT assertion without claiming it is exclusive or reconstructing a historical propagation route. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002909609 SUPPORTS TRANSFER Cytoplasmic target-protein assays and mouse tissue localization support this broad compartment. The authenticated curated node is retained, but its historical IBD placement, tree and MSA were not reconstructed. Current donor records are contextual, not a substitute reconstruction. Supporting Evidence: GO_REF:0000033 file:human/CIB2/CIB2-source-evidence.json |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: Retain the cytoplasmic site of CIB2 interactions. Reason: CIB2 is a soluble intracellular protein that binds the cytoplasmic regions of TMC channels and participates in cellular protein complexes. Endogenous mouse tissue staining and human-protein cellular assays support this broad compartment. Preserve the mouse orthology assertion without claiming it is exclusive or reconstructing a historical propagation route. Supporting Evidence: GO_REF:0000120 file:human/CIB2/CIB2-source-evidence.json |
| GO:0005737 cytoplasm | ISS GO_REF:0000024 | ACCEPT | Summary: Retain the cytoplasmic site of CIB2 interactions. Reason: CIB2 is a soluble intracellular protein that binds the cytoplasmic regions of TMC channels and participates in cellular protein complexes. Endogenous mouse tissue staining and human-protein cellular assays support this broad compartment. Preserve the mouse orthology assertion without claiming it is exclusive or reconstructing a historical propagation route. Supporting Evidence: GO_REF:0000024 file:human/CIB2/CIB2-source-evidence.json |
| GO:0005927 muscle tendon junction | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Retain the source-supported muscle–tendon junction location. Reason: Current mouse Cib2/Q9Z309 has an IDA/PMID:18611855 assertion for this compartment. Actual mouse quadriceps staining places endogenous Cib2 at the sarcolemma and enriches it at muscle–tendon and neuromuscular junctions, with alpha-bungarotoxin defining the latter. This supports the existing orthology inference, not direct human-muscle imaging or an additional mechanotransduction/adhesion mechanism at this site. |
| GO:0007204 positive regulation of cytosolic calcium ion concentration | IDA PMID:23023331 Alterations of the CIB2 calcium- and integrin-binding protei... | MODIFY | Summary: Correct the direction of the measured calcium response. Reason: In PMID:23023331, wild-type human CIB2 expression reduces the ATP-evoked intracellular calcium response in transfected COS7 cells. Mutant comparisons test altered buffering, but do not reverse the direction of the wild-type activity. Negative regulation of cytosolic calcium concentration describes this endpoint more accurately than the preserved positive-regulation source term. The assay does not establish direct ATP binding or universal inhibition of calcium entry. Proposed replacements: negative regulation of cytosolic calcium ion concentration Supporting Evidence: PMID:23023331 decreased the ATP-induced calcium responses |
| GO:0007204 positive regulation of cytosolic calcium ion concentration | IDA PMID:26173970 Novel and recurrent CIB2 variants, associated with nonsyndro... | MODIFY | Summary: Use the negative direction measured for wild-type CIB2. Reason: PMID:26173970 compares wild-type CIB2 and R66W/F91S variants in the ATP-evoked COS7 calcium assay. Wild-type expression attenuates the cytosolic response; these variants retain comparable buffering in that experiment. The endpoint therefore supports negative regulation, not a positive wild-type effect. This is a cellular response assay rather than a purified metal-affinity measurement. Proposed replacements: negative regulation of cytosolic calcium ion concentration Supporting Evidence: |
| GO:0031594 neuromuscular junction | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Retain the source-supported muscle neuromuscular junction location. Reason: Current mouse Cib2/Q9Z309 has an IDA/PMID:18611855 assertion for this compartment. Actual mouse quadriceps staining places endogenous Cib2 at the sarcolemma and enriches it at muscle–tendon and neuromuscular junctions, with alpha-bungarotoxin defining the latter. This supports the existing orthology inference, not direct human-muscle imaging or an additional mechanotransduction/adhesion mechanism at this site. |
| GO:0032420 stereocilium | IBA GO_REF:0000033 | ACCEPT | Summary: Retain stereociliary localization and functional activity. Reason: CIB2 localizes in hair-cell stereocilia, where it associates with TMC proteins and regulates the mechanotransduction apparatus. The curated PAINT assertion has positive target and mouse evidence; historical node placement was not reconstructed. These observations do not prove that every alternative human product targets stereocilia or that the complete protein forms a transmembrane pore. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002909609 SUPPORTS TRANSFER Positive stereociliary localization and TMC-complex function support this site of activity. The authenticated curated node is retained, but its historical IBD placement, tree and MSA were not reconstructed. Current donor records are contextual, not a substitute reconstruction. Supporting Evidence: GO_REF:0000033 file:human/CIB2/CIB2-source-evidence.json |
| GO:0032420 stereocilium | IDA PMID:26173970 Novel and recurrent CIB2 variants, associated with nonsyndro... | ACCEPT | Summary: Retain stereociliary localization and functional activity. Reason: CIB2 localizes in hair-cell stereocilia, where it associates with TMC proteins and regulates the mechanotransduction apparatus. The source tests tagged human CIB2 in neonatal mouse sensory epithelia; its positive targeting is not direct endogenous-human imaging. These observations do not prove that every alternative human product targets stereocilia or that the complete protein forms a transmembrane pore. |
| GO:0032420 stereocilium | IDA PMID:26426422 A Novel C-Terminal CIB2 (Calcium and Integrin Binding Protei... | ACCEPT | Summary: Retain stereociliary localization and functional activity. Reason: CIB2 localizes in hair-cell stereocilia, where it associates with TMC proteins and regulates the mechanotransduction apparatus. The original study uses full-length human CIB2 and the R186W variant in mouse hair-cell explants, with a retained wild-type stereociliary pool. These observations do not prove that every alternative human product targets stereocilia or that the complete protein forms a transmembrane pore. |
| GO:0032420 stereocilium | IEA GO_REF:0000120 | ACCEPT | Summary: Retain stereociliary localization and functional activity. Reason: CIB2 localizes in hair-cell stereocilia, where it associates with TMC proteins and regulates the mechanotransduction apparatus. Mouse Q9Z309 is the authenticated ortholog, with actual primary localization rather than a name-based family transfer. These observations do not prove that every alternative human product targets stereocilia or that the complete protein forms a transmembrane pore. Supporting Evidence: GO_REF:0000120 file:human/CIB2/CIB2-source-evidence.json |
| GO:0032437 cuticular plate | IDA PMID:26426422 A Novel C-Terminal CIB2 (Calcium and Integrin Binding Protei... | KEEP AS NON CORE | Summary: Retain the cuticular-plate pool. Reason: PMID:26426422 shows tagged wild-type human CIB2 in the cell body, cuticular plate and stereocilia of transfected mouse hair cells. Preserve this positive location, while distinguishing it from the better-defined channel-regulatory role at stereocilia. The image does not establish a separate actin-remodeling activity or endogenous human abundance in this compartment. Supporting Evidence: |
| GO:0042383 sarcolemma | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Retain the source-supported muscle sarcolemma location. Reason: Current mouse Cib2/Q9Z309 has an IDA/PMID:18611855 assertion for this compartment. Actual mouse quadriceps staining places endogenous Cib2 at the sarcolemma and enriches it at muscle–tendon and neuromuscular junctions, with alpha-bungarotoxin defining the latter. This supports the existing orthology inference, not direct human-muscle imaging or an additional mechanotransduction/adhesion mechanism at this site. |
| GO:0042803 protein homodimerization activity | IDA PMID:23023331 Alterations of the CIB2 calcium- and integrin-binding protei... | MODIFY | Summary: Retain self-association without requiring dimer stoichiometry. Reason: The original co-immunoprecipitation supports association of differently tagged CIB2 molecules and describes multimerization; it does not count a purified two-subunit particle. Later human CIB2 SEC/NMR and light-scattering experiments observe a monomer under their tested solution conditions and explicitly discuss the earlier positive cellular pull-downs. Identical protein binding preserves the demonstrated association without asserting an obligatory dimer or declaring the older interaction false. Proposed replacements: identical protein binding |
| GO:0044877 protein-containing complex binding | IEA GO_REF:0000107 | MODIFY | Summary: Specify the source-supported integrin interaction. Reason: The mouse source behind this broad complex-binding transfer is PMID:18611855: Cib2 associates with alpha7B–beta1D integrin from muscle lysate, and an isolated alpha7B cytoplasmic peptide binds recombinant Cib2. Integrin binding is the informative shared scope, independently corroborated with human CIB2 in PMID:22779914. This refinement does not assign integrin activation or a universal complex-assembly activity. Proposed replacements: integrin binding Supporting Evidence: GO_REF:0000107 file:human/CIB2/CIB2-source-evidence.json |
| GO:0045494 photoreceptor cell maintenance | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Retain context-dependent photoreceptor maintenance. Reason: The exact donor is mouse Cib2/Q9Z309. The original PMID:23023331 includes mouse retinal localization but its phototransduction/degeneration perturbations are in Drosophila; those endpoints are not relabeled as mouse experiments. Independent mouse genetics in PMID:34162842 shows age-related photoreceptor dysfunction after RPE-specific, but not rod-specific, Cib2 loss. This supports the existing maintenance relationship at a non-cell-autonomous retinal scope, not a separate direct photoreceptor molecular activity or a universal human retinal disease phenotype. Supporting Evidence: GO_REF:0000107 file:human/CIB2/CIB2-source-evidence.json |
| GO:0045494 photoreceptor cell maintenance | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Retain context-dependent photoreceptor maintenance. Reason: The exact donor is mouse Cib2/Q9Z309. The original PMID:23023331 includes mouse retinal localization but its phototransduction/degeneration perturbations are in Drosophila; those endpoints are not relabeled as mouse experiments. Independent mouse genetics in PMID:34162842 shows age-related photoreceptor dysfunction after RPE-specific, but not rod-specific, Cib2 loss. This supports the existing maintenance relationship at a non-cell-autonomous retinal scope, not a separate direct photoreceptor molecular activity or a universal human retinal disease phenotype. Supporting Evidence: GO_REF:0000024 file:human/CIB2/CIB2-source-evidence.json |
| GO:0055074 calcium ion homeostasis | IBA GO_REF:0000033 | ACCEPT | Summary: Retain calcium-homeostasis involvement with assay-specific direction. Reason: The target cellular experiments show reduced ATP-evoked cytosolic calcium responses with wild-type CIB2, while authentic mouse and fly annotations contribute additional homeostasis context. This broad existing process is consistent with calcium binding and experimentally altered calcium handling. It does not imply that every channel-gating effect is a calcium-affinity change or that CIB2 performs ion pumping. The PAINT node is retained; target-independent historical placement was not reconstructed, and neither donor count nor a propagated current record substitutes for that history. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002347490 SUPPORTS TRANSFER Human calcium-response experiments and actual mouse/fly source records support the broad homeostasis role. The authenticated curated node is retained, but its historical IBD placement, tree and MSA were not reconstructed. Current donor records are contextual, not a substitute reconstruction. Supporting Evidence: GO_REF:0000033 file:human/CIB2/CIB2-source-evidence.json |
| GO:0055074 calcium ion homeostasis | IEA GO_REF:0000107 | ACCEPT | Summary: Retain calcium-homeostasis involvement with assay-specific direction. Reason: The target cellular experiments show reduced ATP-evoked cytosolic calcium responses with wild-type CIB2, while authentic mouse and fly annotations contribute additional homeostasis context. This broad existing process is consistent with calcium binding and experimentally altered calcium handling. It does not imply that every channel-gating effect is a calcium-affinity change or that CIB2 performs ion pumping. The current mouse source is explicitly linked to PMID:23023331; human target assays independently corroborate the broad role. Supporting Evidence: GO_REF:0000107 file:human/CIB2/CIB2-source-evidence.json |
| GO:0055074 calcium ion homeostasis | ISS GO_REF:0000024 | ACCEPT | Summary: Retain calcium-homeostasis involvement with assay-specific direction. Reason: The target cellular experiments show reduced ATP-evoked cytosolic calcium responses with wild-type CIB2, while authentic mouse and fly annotations contribute additional homeostasis context. This broad existing process is consistent with calcium binding and experimentally altered calcium handling. It does not imply that every channel-gating effect is a calcium-affinity change or that CIB2 performs ion pumping. The current mouse source is explicitly linked to PMID:23023331; human target assays independently corroborate the broad role. Supporting Evidence: GO_REF:0000024 file:human/CIB2/CIB2-source-evidence.json |
| GO:0071318 cellular response to ATP | IDA PMID:23023331 Alterations of the CIB2 calcium- and integrin-binding protei... | KEEP AS NON CORE | Summary: Retain the experimentally defined ATP-challenge context. Reason: The source applies extracellular ATP to transfected cells and measures the calcium response, with CIB2 modifying its amplitude. That supports the broad response-to-ATP annotation at a contextual level. It does not show ATP recognition, ATP hydrolysis, purinergic receptor activity or a distinct ATP-sensing molecular function of CIB2. Supporting Evidence: |
| GO:0071318 cellular response to ATP | IDA PMID:26173970 Novel and recurrent CIB2 variants, associated with nonsyndro... | KEEP AS NON CORE | Summary: Retain the experimentally defined ATP-challenge context. Reason: The source applies extracellular ATP to transfected cells and measures the calcium response, with CIB2 modifying its amplitude. That supports the broad response-to-ATP annotation at a contextual level. It does not show ATP recognition, ATP hydrolysis, purinergic receptor activity or a distinct ATP-sensing molecular function of CIB2. Supporting Evidence: |
| GO:0071944 cell periphery | IBA GO_REF:0000033 | ACCEPT | Summary: Retain activity at the cell periphery. Reason: The broad PAINT location is consistent with CIB2 binding cytoplasmic regions of membrane channels at stereocilia and with experimentally detected peripheral pools. It is not an assertion that CIB2 spans the membrane or is constitutively membrane-bound in every cell. The historical ancestral placement was not reconstructed; positive target experiments supply independent biological grounding. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002909609 SUPPORTS TRANSFER Peripheral TMC association and positive localization support this broad site of activity. The authenticated curated node is retained, but its historical IBD placement, tree and MSA were not reconstructed. Current donor records are contextual, not a substitute reconstruction. Supporting Evidence: GO_REF:0000033 file:human/CIB2/CIB2-source-evidence.json |
| GO:0072562 blood microparticle | HDA PMID:22516433 Proteomic analysis of microvesicles from plasma of healthy d... | UNDECIDED | Summary: Keep the specific plasma-vesicle proteomics assignment unresolved. Reason: The authentic PMID:22516433 abstract describes isolated plasma microvesicles from healthy donors, but the original target-level CIB2 peptide/table record was not recovered. The bounded publisher request was blocked, and a previously saved supposed XLS was an error response rather than data. General intracellular or membrane-associated CIB2 biology does not verify this exact blood-microparticle assertion. No absence, misattribution or secretion mechanism is inferred. Supporting Evidence: |
| GO:0099106 ion channel regulator activity | ISS PMID:34089643 CIB2 and CIB3 are auxiliary subunits of the mechanotransduct... | NEW | Summary: Add the auxiliary ion-channel regulator activity. Reason: Mouse Cib2 mutations alter resting open probability and channel properties in actual hair-cell electrophysiology, with physical TMC association. In the decisive R186W comparison, currents are TMC2-dependent on a Tmc1-deficient background; tested adaptation remains unchanged. Direct human CIB2–TMC1 binding is independently established by purified-domain ITC, SEC and NMR. This combination supports ortholog transfer of regulation through channel interaction, without claiming a human direct-current assay, autonomous pore formation or proven calcium-driven TMC1 closure. The 2025 eLife ion-conductance results are simulations, not reconstitution. PMID:28663585 independently places endogenous mouse CIB2 in stereocilia and shows human CIB2–TMC1 association by cellular FRET, with separate mouse Y2H and loss-of-current experiments. Supporting Evidence: file:human/CIB2/CIB2-source-evidence.json |
| GO:0031267 small GTPase binding | IPI PMID:34162842 CIB2 regulates mTORC1 signaling and is essential for autopha... | NEW | Summary: Add the demonstrated RHEB small-GTPase interaction. Reason: Human CIB2 interacts with RHEB in NanoSPD and co-immunoprecipitation experiments, with preferential association with nucleotide-empty or GDP-loaded RHEB under the tested conditions. Immobilized nucleotide-loaded RHEB was incubated with CIB2-containing cell lysate, so this is not a purified binary-affinity measurement. RHEB/Q15382 is an authenticated small GTPase. The term records the performed binding activity, not a demonstrated GDI, GAP, guanine-nucleotide exchange or direct mTOR catalytic-inhibitor mechanism. |
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Download this section (compressed HTML)Q: How do CIB2 metal occupancy and its two TMC-contact surfaces control opening of native human TMC1-containing channels, independently of changes in channel localization?
Q: Does CIB2 directly alter RHEB nucleotide exchange or hydrolysis, or does its effect on mTORC1 require Raptor or another partner?
Q: Which full-length CIB2 products bind PDZ proteins in native tissues, and does the alternative O75838-2 tail redirect these interactions?
Q: What conditions permit CIB2 self-association, and can native complexes distinguish direct oligomerization from association through TMC or other partners?
Q: Can the original plasma-microvesicle target peptide table be recovered to resolve the source-specific CIB2 blood-microparticle annotation?
Q: Which hearing-process granularity best captures CIB2’s performed auxiliary channel work: regulation of mechanotransduction, broader sensory perception of sound, or GO:0050910 detection of mechanical stimulus involved in sensory perception of sound? Current same-role auxiliary comparators and target annotations do not settle that convention.
Experiment: Compare matched human TMC1 channel complexes containing wild-type or interface-selective CIB2 variants, measuring membrane abundance and mechanically evoked currents separately while controlling intracellular calcium and magnesium.
Experiment: Reconstitute purified human CIB2, RHEB and defined Raptor–mTORC1 complexes, independently measuring nucleotide exchange, hydrolysis, binding and substrate phosphorylation to distinguish binding from catalytic regulation.
Experiment: Test all authenticated CIB2 products with matched expression and metal conditions against selected PDZ domains, then verify the strongest full-length associations in cells with endogenous interaction assays.
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