CAPSL (calcyphosin-like protein) is a small (208 aa) EF-hand protein of the calcyphosin family. It has four EF-hand domains, of which the first two carry canonical calcium-coordinating loops. CAPSL is expressed in multiciliated epithelia. A 2026 cryo-electron tomography preprint on bovine tracheal cilia identifies CAPSL as a microtubule inner protein (MIP) that lines the lumen of the microtubule doublets of the ciliary transition zone, where it forms a pseudo-helical spiral. The same study reports that CAPSL stabilizes microtubules in vitro. Antibody staining also detects CAPSL in the cytoplasm and nucleus of cultured cells. Its EF-hands point away from the tubulin interface, and nobody has yet tested whether calcium regulates its microtubule role. In genetic studies, knockdown in human retinal microvascular endothelial cells and endothelial-specific knockout in mouse retina impair angiogenesis and reduce MYC protein levels, and CAPSL variants have been reported in familial exudative vitreoretinopathy. Knockout in 3T3-L1 preadipocytes alters adipogenic differentiation. The mechanisms that link CAPSL to these phenotypes are unknown.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005509 calcium ion binding | IEA GO_REF:0000002 | ACCEPT | Summary: Calcium binding is supported by the EF-hand architecture of CAPSL and by the solved calcium-loaded structure of the related calcyphosin, which belongs to the same PANTHER family. Reason: Human CAPSL has four PROSITE EF-hand domains. EF-hands 1 and 2 match the canonical EF_HAND_1 calcium-binding loop motif (PS00018, two hits), and PROSITE-ProRule assigns calcium-coordinating positions 52-63 and 88-99. CAPSL sits in PANTHER family PTHR34524, subfamily SF5 (calcyphosin-like protein). Human calcyphosin (CAPS, SF2) in the same family has a calcium-loaded crystal structure with paired EF-hands (PMID:18775726). The mouse and bovine SF5 orthologs are 95 to 96 percent identical to human CAPSL. The InterPro2GO inference is therefore sound. No direct calcium-affinity measurement exists for CAPSL, and EF-hands 3 and 4 may not bind calcium. It is retained as a core molecular property even though its physiological role is unknown. Supporting Evidence: file:human/CAPSL/CAPSL-uniprot.txt /note="EF-hand 1" file:human/CAPSL/CAPSL-uniprot.txt /ligand="Ca(2+)" PMID:18775726 The crystal structure of Ca(2+)-loaded calcyphosine was determined up to 2.65 A resolution and reveals a protein containing two pairs of Ca(2+)-binding EF-hand motifs. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: CAPSL is detected in the cytoplasm, but its best-characterised position is inside the microtubule doublets of the ciliary transition zone. Reason: The UniProt subcellular location is a curator inference (ECO:0000305). The cytoplasm-and-nucleus statement in the FEVR study cites the Human Protein Atlas rather than an experiment of that study. The study's own immunocytochemistry only checked that the L83F variant did not change CAPSL localization. The cytoplasmic pool is plausible but its function is unknown. The precise native location reported for CAPSL is the lumen of transition-zone doublet microtubules (see the organelle row), and the ciliary transition zone is not a descendant of cytoplasm in GO. Cytoplasm is therefore kept as a true but non-core location. It is not refined, because the cytoplasmic pool itself has no more specific supported location. Supporting Evidence: PMID:39264149 CAPSL is localized in both the cytoplasm and the nucleus of cells (https://www.proteinatlas.org/), and we then further verified whether these variants have any impact on CAPSL localization. file:human/CAPSL/CAPSL-deep-research-falcon.md Antibody-based spatial profiling localized CAPSL at protein level to the **cilia and cell body of ciliated fallopian-tube epithelial cells**. |
| GO:0043226 organelle | IEA GO_REF:0000117 | MODIFY | Summary: Organelle is correct but too general. The supported organelle localization is the ciliary transition zone, which is a descendant of organelle via cilium. Reason: The ARBA rule supplies no specific compartment. The cryo-ET structure of mammalian (bovine tracheal) transition-zone doublets assigns CAPSL as the lumenal MIP of that segment. Bovine CAPSL (A6H790) is in the same PANTHER subfamily (PTHR34524:SF5) as human CAPSL and is 96 percent identical over all 208 residues, so the localization transfers within the ortholog group. GO:0035869 ciliary transition zone is_a-descends from GO:0043226 via GO:0005929 cilium. It is the specific supported term. The evidence is a preprint whose full text could not be inspected here, so the replacement should be confirmed when the peer-reviewed version appears. The nuclear staining cited from the Human Protein Atlas is not strong enough to add a nucleus term. Proposed replacements: ciliary transition zone Supporting Evidence: DOI:10.64898/2026.06.11.731632 We identify the calcium-binding protein CAPSL as a lumenal MIP that forms a pseudo-helical spiral and stabilizes microtubules |
| GO:0008017 microtubule binding | IDA DOI:10.64898/2026.06.11.731632 | NEW | Summary: Proposed new annotation. CAPSL binds the lumenal surface of transition-zone doublet microtubules and stabilizes microtubules in vitro. Reason: The cryo-ET reconstruction places CAPSL as a lumenal microtubule inner protein that contacts tubulin in an ordered, 8-nm-periodic pseudo-helical array, and the abstract reports microtubule stabilization in vitro. This is the gene product's own physical activity, not a downstream phenotype. Native structural data are from the bovine ortholog in the same PANTHER subfamily (SF5, 96 percent identical). The Falcon report states that purified human CAPSL decorated microtubules. That detail could not be checked against the preprint full text and is not relied on here. Microtubule binding is chosen over a structural-constituent term because the abstract demonstrates binding and stabilization but not a required structural role in vivo. The annotation should be confirmed against the peer-reviewed version. Supporting Evidence: DOI:10.64898/2026.06.11.731632 We identify the calcium-binding protein CAPSL as a lumenal MIP that forms a pseudo-helical spiral and stabilizes microtubules |
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Download this section (compressed HTML)Q: Does calcium occupancy of EF-hands 1 and 2 change CAPSL binding to the microtubule lumen or its self-association in the transition-zone spiral?
Q: Is the endothelial requirement for CAPSL in retinal angiogenesis, which acts through lowered MYC protein, related to a microtubule-associated function in endothelial cells, or does it reflect a separate cytoplasmic or nuclear pool? Human curators have not annotated the endothelial phenotypes that MGI captured for mouse Capsl. Should GO capture them as process participation, or only as phenotype?
Experiment: Knock out CAPSL in differentiated human airway multiciliated cultures and analyse transition-zone doublet ultrastructure by cryo-ET, ciliary gating and beat, with rescue by tubulin-interface and EF-hand loop mutants.
Hypothesis: CAPSL is required for the mechanical integrity of transition-zone doublets, and calcium binding modulates this role.
Experiment: Measure calcium affinity of recombinant CAPSL (ITC or fluorescence titration) and test calcium dependence of its microtubule binding and stabilization in vitro.
Hypothesis: EF-hands 1 and 2 bind calcium with physiologically relevant affinity, and calcium binding changes CAPSL interaction with microtubules.
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