KIF7 is a 1343-residue member of the kinesin-4 family and the vertebrate counterpart of Drosophila Costal-2, with which it shares PANTHER family PTHR24115 as a sister subfamily. It has an N-terminal kinesin motor domain, a coiled-coil stalk that supports homodimerisation, and a long C-terminal region carrying the GLI-binding and NPHP1-binding determinants. Despite the intact motor domain, KIF7 is not a transport motor: purified KIF7 binds microtubules with high affinity but shows no detectable movement, because it cannot release ADP in response to microtubule binding. Instead it binds the plus ends of growing microtubules, where it slows growth and promotes catastrophe in an ATP-hydrolysis-dependent manner. In cells this makes KIF7 the organiser of the distal tip of the primary cilium: it limits cilium length, keeps the axoneme correctly modified and stable, and creates a single tip compartment. KIF7 concentrates at the ciliary base when Hedgehog signalling is off and redistributes to the tip when the pathway is activated, and it tethers the GLI transcription factors together with their inhibitor SUFU at that tip; it also delivers the prolyl hydroxylase P4HA2 there. Through this one scaffolding activity KIF7 acts in both directions on the pathway downstream of Smoothened - restraining ligand-independent GLI2 activation and preventing ectopic activation of GLI-SUFU complexes scattered along the axoneme, while also promoting signalling by driving SUFU turnover and SUFU-GLI dissociation and by protecting full-length GLI3 from processing into its repressor form. It is not required for intraflagellar transport or for entry of pathway components into the cilium. In humans, loss of KIF7 causes a group of ciliopathies - acrocallosal syndrome, hydrolethalus syndrome 2, Joubert syndrome 12 and Al-Gazali-Bakalinova syndrome - with polydactyly, corpus callosum and other brain malformations, and skeletal defects, and KIF7 missense alleles act as modifiers across the wider ciliopathy spectrum.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003777 microtubule motor activity | IBA GO_REF:0000033 | MODIFY | Summary: The PAINT node PTN000648413 asserts microtubule motor activity across the kinesin superfamily, and that node placement is sound: nearly every extant member sampled is a processive motor. KIF7 is the documented exception. Purified recombinant KIF7 binds microtubules but shows no detectable movement, and the same is true of Drosophila Costal-2, so the loss is a property of the whole KIF7/Costa clade rather than of human KIF7 alone (PMID:24952464, PMID:29351996). Reason: The argument here is not with the IBD node but with whether this descendant inherited the activity. Yue et al. assayed all four kinesin-4 branches side by side and found KIF4 and KIF21 fast and processive, KIF27 slow and processive, and KIF7 and Cos2 immotile - and traced KIF7 immotility to an inability to release ADP on microtubule binding, i.e. a break in the motor's chemomechanical cycle rather than a loss of microtubule affinity (PMID:29351996). He et al. reached the same conclusion with purified KIF7 on dynamic microtubules (PMID:24952464). GO:0003777 is defined as "A motor activity that generates movement along a microtubule, driven by ATP hydrolysis", so it is contradicted. What survives is the microtubule interaction, and specifically plus-end binding, which is the activity the same experiments do demonstrate. Both replacement terms are already carried by this gene in other rows or are proposed here; the motor reading is what must go. Propagation Review Root cause: PROPAGATION BAD Failure modes: PSEUDO OR SUBACTIVITY LOSS FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN000648413 SUPPORTS SOURCE BUT NOT TARGET Superfamily-level motor node. The assertion is right for the node and for most descendants; the KIF7/Costa subfamily lost processive stepping while keeping microtubule binding, so the term should not descend here. Proposed replacements: microtubule plus-end binding microtubule binding Supporting Evidence: PMID:24952464 KIF7 can interact directly with microtubules but lacks detectable motility PMID:24952464 Purified recombinant Kif7 binds the plus ends of growing microtubules in vitro, where it reduces the rate of microtubule growth and increases the frequency of microtubule catastrophe. PMID:29351996 KIF4 and KIF21 motors are fast and processive, KIF7 and its Drosophila melanogaster homologue Costal2 (Cos2) are immotile, and KIF27 is slow and processive. PMID:29351996 The mechanistic basis of immotile KIF7 behavior arises from an inability to release adenosine diphosphate in response to microtubule binding |
| GO:0003777 microtubule motor activity | IDA PMID:21633164 Mutations in KIF7 link Joubert syndrome with Sonic Hedgehog ... | MODIFY | Summary: Dafinger et al. is the source of this IDA. Its abstract calls KIF7 "a putative ciliary motor protein" and its cell-biological result is that KIF7 knockdown perturbs tubulin acetylation and microtubule dynamics - a microtubule-directed activity, read at the time as motility (PMID:21633164). Purified-protein work published afterwards shows KIF7 does not move along microtubules (PMID:24952464, PMID:29351996). Reason: This is not a case of second-guessing an assay that the cached abstract happens not to show. The 2011 paper frames motor activity as putative, and two later studies measured motility directly on purified KIF7 - single-molecule imaging plus microtubule gliding in Yue et al., TIRF assays on dynamic microtubules in He et al. - and found none. The underlying observation the IDA rests on (KIF7 acting on microtubules and their post-translational state) is sound and is retained by replacing the term with microtubule plus-end binding, the activity the purified protein does have. Even the motor-domain requirement reported for ciliary-tip targeting (PMID:19666503) is consistent with this: the domain is needed because it binds microtubules, not because it walks. Proposed replacements: microtubule plus-end binding microtubule binding Supporting Evidence: PMID:21633164 Interestingly, KIF7 is a known regulator of Hedgehog signaling and a putative ciliary motor protein. PMID:21633164 These cellular phenotypes likely resulted from abnormal tubulin acetylation and microtubular dynamics. PMID:24952464 KIF7 can interact directly with microtubules but lacks detectable motility PMID:29351996 KIF4 and KIF21 motors are fast and processive, KIF7 and its Drosophila melanogaster homologue Costal2 (Cos2) are immotile, and KIF27 is slow and processive. PMID:19666503 Activation of the Shh pathway promotes trafficking of Kif7-eGFP from the base to the tip of the cilium, and localization to the tip of the cilium is disrupted in a motor domain mutant. |
| GO:0003777 microtubule motor activity | IEA GO_REF:0000002 | MODIFY | Summary: InterPro-driven mapping from the kinesin motor domain signatures IPR001752, IPR019821 and IPR027640. KIF7 does carry an intact kinesin motor domain (UniProt DOMAIN 15..349) and does bind microtubules through it, but the domain-to-motility inference fails for this subfamily. Reason: The domain premise is correct and the microtubule-binding consequence of it is correct; only the motility consequence is wrong. Keeping the defensible part means replacing GO:0003777 with GO:0008017 microtubule binding, which this same InterPro signature already supplies in a separate row. Removal would discard a true statement along with the false one. Proposed replacements: microtubule binding Supporting Evidence: PMID:24952464 KIF7 can interact directly with microtubules but lacks detectable motility PMID:29351996 KIF4 and KIF21 motors are fast and processive, KIF7 and its Drosophila melanogaster homologue Costal2 (Cos2) are immotile, and KIF27 is slow and processive. file:human/KIF7/KIF7-uniprot.txt Kinesin motor |
| GO:0005515 protein binding | IPI PMID:19592253 The mammalian Cos2 homolog Kif7 plays an essential role in m... | MODIFY | Summary: Co-precipitation of KIF7 with human GLI3, one of five pathway partners reported together in Endoh-Yamagami et al. The same paper shows the functional consequence: KIF7 is required for efficient GLI3 localisation to cilia in response to Hh and for GLI3 repressor processing (PMID:19592253). Reason: A bare protein-binding row carries no functional information, but this interaction has an established molecular consequence, so the policy asks for MODIFY rather than removal. KIF7 does not act on GLI catalytically and does not carry it: it holds the GLI-SUFU complex in one place. He et al. show that without KIF7 the Gli-Sufu complex appears in ectopic tip-like compartments scattered along the axoneme instead of at the single distal tip, while entry into the cilium is unaffected (PMID:24952464). Yue et al. reach the same description from the biochemistry, proposing that immotile KIF7 and Cos2 work as microtubule-based tethers of signalling complexes (PMID:29351996). That is protein-macromolecule adaptor activity, and it is the term the pan-metazoan Hedgehog module already assigns to the KIF7 ciliary-tip annoton. For GLI3 specifically the downstream readout is documented twice over: impaired GLI3 processing is also what is seen in tissue from patients carrying KIF7 mutations (PMID:21552264). Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: PMID:19592253 We also demonstrate a requirement for Kif7 in the efficient localization of Gli3 to cilia in response to Hh and for the processing of Gli3 to its repressor form. PMID:19592253 These results suggest a role for Kif7 in coordinating Hh signal transduction at the tip of cilia and preventing Gli3 cleavage into a repressor form in the presence of Hh. PMID:24952464 indicating that KIF7 is required to restrict Gli-Sufu complexes to the distal end of the cilium PMID:29351996 We suggest that evolutionarily selected sequence differences enable immotile KIF7 and Cos2 motors to function not as transporters but as microtubule-based tethers of signaling complexes. PMID:21552264 Consistent with a role of KIF7 in Hedgehog signaling, we show deregulation of most GLI transcription factor targets and impaired GLI3 processing in tissues from individuals with KIF7 mutations. |
| GO:0005515 protein binding | IPI PMID:19592253 The mammalian Cos2 homolog Kif7 plays an essential role in m... | MODIFY | Summary: Co-precipitation of KIF7 with mouse Gli1 from the same panel (PMID:19592253). Independent work in mouse and zebrafish shows KIF7 binds Gli proteins and governs their stability, processing and sub-compartmental position (PMID:19549984, PMID:24339784). Reason: A bare protein-binding row carries no functional information, but this interaction has an established molecular consequence, so the policy asks for MODIFY rather than removal. KIF7 does not act on GLI catalytically and does not carry it: it holds the GLI-SUFU complex in one place. He et al. show that without KIF7 the Gli-Sufu complex appears in ectopic tip-like compartments scattered along the axoneme instead of at the single distal tip, while entry into the cilium is unaffected (PMID:24952464). Yue et al. reach the same description from the biochemistry, proposing that immotile KIF7 and Cos2 work as microtubule-based tethers of signalling complexes (PMID:29351996). That is protein-macromolecule adaptor activity, and it is the term the pan-metazoan Hedgehog module already assigns to the KIF7 ciliary-tip annoton. Cheung et al. found that KIF7 physically interacts with Gli transcription factors and controls their proteolysis and stability, acting in both directions (PMID:19549984), and in zebrafish Kif7 binds Gli1 and Gli2a and sequesters them, with Drosophila Cos2 able to substitute for Kif7 outright (PMID:24339784) - the clearest possible statement that this is the scaffold activity of Cos2 rather than a generic contact. Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: PMID:19549984 Similar to Cos2, Kif7 physically interacted with Gli transcription factors and controlled their proteolysis and stability, and acted both positively and negatively in Hh signaling. PMID:24339784 We show that Kif7 interacts with both Gli1 and Gli2a and suggest that it functions to sequester Gli proteins in the cytoplasm, in a manner analogous to the regulation of Ci by Cos2 in Drosophila. PMID:24339784 Moreover, we show that Drosophila Costal2 can substitute for Kif7, suggesting a conserved mode of action of the two proteins. PMID:24952464 indicating that KIF7 is required to restrict Gli-Sufu complexes to the distal end of the cilium |
| GO:0005515 protein binding | IPI PMID:19592253 The mammalian Cos2 homolog Kif7 plays an essential role in m... | REMOVE | Summary: Co-precipitation of KIF7 with human SMO, reported in the same five-partner panel as the GLI and SUFU contacts (PMID:19592253; UniProt SUBUNIT "Interacts with GLI1, GLI2, GLI3, SMO and SUFU"). Unlike the GLI and SUFU contacts, no molecular consequence of a vertebrate KIF7-SMO contact has been established. Reason: The interaction itself is not disputed and removal does not say it is false. The problem is that a bare protein-binding row is uninformative and, for this pair, nothing more informative is supported. KIF7 acts genetically downstream of SMO (PMID:19666503), which is a pathway-order statement, not evidence that KIF7 tethers SMO to anything; and He et al. found KIF7 still at cilia tips in cells lacking Smo, so KIF7 localisation does not depend on SMO either (PMID:24952464). Assigning adaptor activity on the strength of this row alone would be inventing a function from interaction evidence. The Drosophila Costal-2-Smoothened tail interaction is a real scaffold recruitment step, but it is curated in the Drosophila arm of the module and does not license the vertebrate claim. Supporting Evidence: file:human/KIF7/KIF7-uniprot.txt Interacts with GLI1, GLI2, GLI3, SMO and SUFU PMID:19666503 we show that, similar to Drosophila and zebrafish Cos2, mouse Kif7 acts downstream of Smo and upstream of Gli2 and has both negative and positive roles in Shh signal transduction PMID:24952464 KIF7 was also present at cilia tips in MEFs derived from mutant embryos that lack Smo or Gli2 and Gli3, indicating that KIF7 is targeted to cilia independently of Shh pathway proteins |
| GO:0005515 protein binding | IPI PMID:19592253 The mammalian Cos2 homolog Kif7 plays an essential role in m... | MODIFY | Summary: Co-precipitation of KIF7 with mouse Sufu (PMID:19592253). This is the best-characterised of the KIF7 contacts: in growth-plate chondrocytes and in keratinocytes the positive arm of KIF7 function runs entirely through relieving SUFU inhibition of GLI (PMID:21795282, PMID:23034632). Reason: A bare protein-binding row carries no functional information, but this interaction has an established molecular consequence, so the policy asks for MODIFY rather than removal. KIF7 does not act on GLI catalytically and does not carry it: it holds the GLI-SUFU complex in one place. He et al. show that without KIF7 the Gli-Sufu complex appears in ectopic tip-like compartments scattered along the axoneme instead of at the single distal tip, while entry into the cilium is unaffected (PMID:24952464). Yue et al. reach the same description from the biochemistry, proposing that immotile KIF7 and Cos2 work as microtubule-based tethers of signalling complexes (PMID:29351996). That is protein-macromolecule adaptor activity, and it is the term the pan-metazoan Hedgehog module already assigns to the KIF7 ciliary-tip annoton. The genetics is unusually clean here: halving the Sufu dose restores normal pathway activity and chondrocyte development in Kif7-null mice, which places KIF7 upstream of SUFU as a regulator of the SUFU-GLI complex rather than as a substrate or a transporter of it (PMID:21795282). In keratinocytes KIF7 promotes pathway activity by dissociating the SUFU-GLI2 complex (PMID:23034632), and in zebrafish by promoting Gli2a release from Sufu (PMID:24339784). Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: PMID:21795282 Kif7 plays a role in the turnover of Sufu and the exclusion of Sufu-Gli complexes from the primary cilium. PMID:21795282 Importantly, halving the dose of Sufu restores normal hedgehog pathway activity and chondrocyte development in Kif7-null mice, demonstrating that the positive role of Kif7 is to restrict the inhibitory activity of Sufu. PMID:23034632 Kif7 possesses Sufu-dependent and -independent regulatory functions in Hh signaling: while it promotes Hh pathway activity through the dissociation of Sufu-Gli2 complex, it also contributes to the repression of Hh target genes in the absence of Sufu. PMID:24339784 We also show that zebrafish Kif7 potentiates Gli2a activity by promoting its dissociation from the Suppressor of Fused (Sufu) protein PMID:24952464 indicating that KIF7 is required to restrict Gli-Sufu complexes to the distal end of the cilium |
| GO:0005515 protein binding | IPI PMID:21633164 Mutations in KIF7 link Joubert syndrome with Sonic Hedgehog ... | REMOVE | Summary: A single co-immunoprecipitation of KIF7 with nephrocystin-1 (NPHP1), reported alongside the mapping of a KIF7 region sufficient for the interaction (UniProt REGION 513..775). No molecular or cellular consequence of the pair has been established (PMID:21633164). Reason: The interaction is plausible - both proteins are Joubert syndrome products and the paper was looking for a shared ciliary mechanism - and removal is not a claim that it is false. But the row is a bare protein-binding assertion with no functional content, and nothing in the paper supports a more informative molecular function for KIF7 with respect to NPHP1: the cilium, centrosome and Golgi phenotypes reported there are attributed to microtubule dynamics, which is captured by other rows. Per the generic-protein-binding policy this is the removal case rather than the MODIFY case. Supporting Evidence: PMID:21633164 We found that KIF7 co-precipitated with nephrocystin-1. PMID:21633164 Further, knockdown of KIF7 expression in cell lines caused defects in cilia formation and induced abnormal centrosomal duplication and fragmentation of the Golgi network. file:human/KIF7/KIF7-uniprot.txt Sufficient for interaction with NPHP1 |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MODIFY | Summary: KIF7-P4HA2 (prolyl 4-hydroxylase subunit alpha-2) interaction detected by the BioPlex affinity-purification interactome. The pair has since been validated by co-immunoprecipitation, domain mapping and in vitro reconstitution, with KIF7 acting as the scaffold that delivers P4HA2 to the ciliary tip and couples it to the SUFU-GLI complex (PMID:38909089). Reason: Three high-throughput screens finding the same interaction would not by itself justify anything more than removal of an uninformative row. What changes the call is that the interaction was subsequently validated and given a mechanism, in a paper that explicitly credits these three screens as its prior support (PMID:38909089). In that work P4HA2 binds KIF7 directly - and only KIF7, not GLI1 or SUFU - through the KIF7 GLI-binding domain; KIF7 knockdown reduces P4HA2 association with GLI1 and with SUFU; and in KIF7-knockout cells P4HA2 no longer reaches the cilium at all. The authors state the conclusion in the terms GO uses: KIF7 serves as a scaffold protein. So the informative molecular function behind these rows is protein-macromolecule adaptor activity, the same activity that covers the GLI and SUFU contacts and the same term the Hedgehog module assigns to the KIF7 annoton. Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: PMID:38909089 three independent proteome interactome studies have detected the interaction between P4HA2 and KIF7 PMID:38909089 Notably, a strong direct interaction was observed between P4HA2 and KIF7, while no significant or direct interaction was detected between P4HA2 and GLI1 or SUFU PMID:38909089 suggesting that the ciliary localization of P4HA2 is dependent on KIF7 PMID:38909089 In summary, KIF7 serves as a scaffold protein, facilitating the ciliary localization of P4HA2 and its association with other components, thereby regulating the impact of P4HA2 on the Hh signaling pathway. PMID:38909089 Additionally, KIF7, acting as a key scaffold protein, is involved in the post-translational modification of the Hh pathway component, facilitating the hydroxylation of key proline residues in SUFU. |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | MODIFY | Summary: KIF7-P4HA2 (prolyl 4-hydroxylase subunit alpha-2) interaction detected by the OpenCell endogenous-tagging interactome. The pair has since been validated by co-immunoprecipitation, domain mapping and in vitro reconstitution, with KIF7 acting as the scaffold that delivers P4HA2 to the ciliary tip and couples it to the SUFU-GLI complex (PMID:38909089). Reason: Three high-throughput screens finding the same interaction would not by itself justify anything more than removal of an uninformative row. What changes the call is that the interaction was subsequently validated and given a mechanism, in a paper that explicitly credits these three screens as its prior support (PMID:38909089). In that work P4HA2 binds KIF7 directly - and only KIF7, not GLI1 or SUFU - through the KIF7 GLI-binding domain; KIF7 knockdown reduces P4HA2 association with GLI1 and with SUFU; and in KIF7-knockout cells P4HA2 no longer reaches the cilium at all. The authors state the conclusion in the terms GO uses: KIF7 serves as a scaffold protein. So the informative molecular function behind these rows is protein-macromolecule adaptor activity, the same activity that covers the GLI and SUFU contacts and the same term the Hedgehog module assigns to the KIF7 annoton. Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: PMID:38909089 three independent proteome interactome studies have detected the interaction between P4HA2 and KIF7 PMID:38909089 Notably, a strong direct interaction was observed between P4HA2 and KIF7, while no significant or direct interaction was detected between P4HA2 and GLI1 or SUFU PMID:38909089 suggesting that the ciliary localization of P4HA2 is dependent on KIF7 PMID:38909089 In summary, KIF7 serves as a scaffold protein, facilitating the ciliary localization of P4HA2 and its association with other components, thereby regulating the impact of P4HA2 on the Hh signaling pathway. PMID:38909089 Additionally, KIF7, acting as a key scaffold protein, is involved in the post-translational modification of the Hh pathway component, facilitating the hydroxylation of key proline residues in SUFU. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MODIFY | Summary: KIF7-P4HA2 (prolyl 4-hydroxylase subunit alpha-2) interaction detected by the multimodal cell-map interactome. The pair has since been validated by co-immunoprecipitation, domain mapping and in vitro reconstitution, with KIF7 acting as the scaffold that delivers P4HA2 to the ciliary tip and couples it to the SUFU-GLI complex (PMID:38909089). Reason: Three high-throughput screens finding the same interaction would not by itself justify anything more than removal of an uninformative row. What changes the call is that the interaction was subsequently validated and given a mechanism, in a paper that explicitly credits these three screens as its prior support (PMID:38909089). In that work P4HA2 binds KIF7 directly - and only KIF7, not GLI1 or SUFU - through the KIF7 GLI-binding domain; KIF7 knockdown reduces P4HA2 association with GLI1 and with SUFU; and in KIF7-knockout cells P4HA2 no longer reaches the cilium at all. The authors state the conclusion in the terms GO uses: KIF7 serves as a scaffold protein. So the informative molecular function behind these rows is protein-macromolecule adaptor activity, the same activity that covers the GLI and SUFU contacts and the same term the Hedgehog module assigns to the KIF7 annoton. Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: PMID:38909089 three independent proteome interactome studies have detected the interaction between P4HA2 and KIF7 PMID:38909089 Notably, a strong direct interaction was observed between P4HA2 and KIF7, while no significant or direct interaction was detected between P4HA2 and GLI1 or SUFU PMID:38909089 suggesting that the ciliary localization of P4HA2 is dependent on KIF7 PMID:38909089 In summary, KIF7 serves as a scaffold protein, facilitating the ciliary localization of P4HA2 and its association with other components, thereby regulating the impact of P4HA2 on the Hh signaling pathway. PMID:38909089 Additionally, KIF7, acting as a key scaffold protein, is involved in the post-translational modification of the Hh pathway component, facilitating the hydroxylation of key proline residues in SUFU. |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: ATP binding inferred from the kinesin motor domain signatures IPR001752 and IPR019821. KIF7 has an intact P-loop kinesin motor domain and measurably hydrolyses ATP, and its effect on microtubule dynamics is ATP-hydrolysis dependent (PMID:24952464, PMID:29351996). Reason: Unlike the motility inference from the same domain, nucleotide binding is directly confirmed for KIF7: steady-state ATPase activity was measured on purified KIF7 with and without microtubules, and the catastrophe-promoting activity requires ATP hydrolysis - in the non-hydrolysable analogue AMP-PNP, KIF7 had no detectable effect on catastrophe frequency. Accepted as core, since nucleotide turnover is what licenses the plus-end activity. Supporting Evidence: PMID:24952464 Together, our in vitro analysis suggests that the plus-end-associated KIF7 promotes catastrophe and inhibits microtubule growth in an ATP-hydrolysis dependent manner. PMID:24952464 In the presence of AMP-PNP (2 mM), 70 nM KIF7560-GFP had no detectable effect on the catastrophe frequency PMID:29351996 For immotile KIF7, very little microtubule-dependent stimulation of ATPase activity was observed. |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Cytoplasm as the active compartment, from the kinesin-superfamily PAINT node. There is a real cytoplasmic KIF7 pool: endogenous zebrafish Kif7 forms cytoplasmic puncta that disperse on pathway activation (PMID:24339784), and KIF7 co-localises with P4HA2 in the cytoplasm before stimulation (PMID:38909089). Reason: The annotation is true but does not locate the function. Everything that distinguishes KIF7 from other kinesins happens in the cilium, at the distal tip, and the ciliary compartment is where both the GLI-SUFU tethering and the axonemal plus-end activity occur. The cytoplasmic pool is a pre-activation reservoir that traffics into the cilium on stimulation, which makes cytoplasm a genuine but secondary location. Kept rather than removed because the zebrafish work makes the cytoplasmic pool a substantive observation, and because the Drosophila arm of the same pathway runs the equivalent Costal-2 step on a cytoplasmic complex. Supporting Evidence: PMID:24339784 Notably, we find that endogenous Kif7 protein accumulates not only in the primary cilium, as previously observed in mammalian cells, but also in cytoplasmic puncta that disperse in response to Hh pathway activation. PMID:38909089 We found that P4HA2-EGFP co-localized with KIF7-BFP in cytoplasm. |
| GO:0005871 kinesin complex | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Kinesin complex membership from the superfamily PAINT node. KIF7 does dimerise - UniProt records "Can form homodimers and interacts with microtubules", the protein has the canonical coiled-coil stalk (UniProt COILED 480..542), and mouse Kif7 carries an experimental identical-protein-binding annotation from He et al. Reason: The structural claim holds: a coiled-coil-mediated kinesin homodimer satisfies the first clause of the GO:0005871 definition. But the definition goes on to describe kinesin complexes as generally possessing "a force-generating enzymatic activity, or motor, which converts the free energy of the gamma phosphate bond of ATP into mechanical work" - which is exactly what KIF7 does not do. Retaining the row as non-core records the dimer without importing the motor-complex connotation, and without asserting the light-chain-bearing transport complexes the term was written for. KIF7 dimerisation matters mechanistically, but as the basis of plus-end binding rather than as membership of a transport machine. Supporting Evidence: file:human/KIF7/KIF7-uniprot.txt Can form homodimers and interacts with microtubules file:human/KIF7/KIF7-uniprot.txt COILED 480..542 |
| GO:0005874 microtubule | IBA GO_REF:0000033 | ACCEPT | Summary: Microtubule as the compartment in which KIF7 is active, from the superfamily PAINT node. This is directly confirmed: purified KIF7 binds the plus ends of growing microtubules, and in cells the relevant microtubules are the axonemal ones whose distal ends define the cilium tip (PMID:24952464). Reason: One of the few superfamily-level assertions that transfers to KIF7 without qualification, and it is core: the microtubule is not incidental scenery but the substrate KIF7 acts on and the surface on which it tethers the GLI-SUFU complex. Reactome states the same, crediting He et al. A more specific location is not available in the component ontology - plus-end specificity belongs in the molecular function, where it is proposed as GO:0051010. Supporting Evidence: PMID:24952464 Purified recombinant Kif7 binds the plus ends of growing microtubules in vitro, where it reduces the rate of microtubule growth and increases the frequency of microtubule catastrophe. PMID:24952464 Here we show that Kif7 localizes to the cilium tip, the site of microtubule plus ends, where it limits cilium length and controls cilium structure. Reactome:R-HSA-5610733 KIF7, the human ortholog of Drosophila COS2, is a kinesin-4 motor protein that binds directly to the plus ends of axonemal microtubules and inhibits their growth in an ATP-dependent manner |
| GO:0005929 cilium | IDA GO_REF:0000052 | ACCEPT | Summary: Cilium localisation from curated immunofluorescence (HPA, GO_REF:0000052). Independently established in mouse and human cells by several groups (PMID:19592253, PMID:19666503, PMID:24952464). Reason: Correct and core. KIF7 is a ciliary protein in every system in which it has been looked at, and its function is cilium-dependent: mouse Kif7 activity requires the presence of cilia. The sibling GO:0097542 ciliary tip rows give the precise sub-compartment; accepting the parent term alongside them is appropriate because KIF7 is also found at the ciliary base in the unstimulated state, so cilium is the correct umbrella statement rather than a vague one. Supporting Evidence: PMID:19592253 We show that Kif7 accumulates at the distal tip of the primary cilia in a Hh-dependent manner. PMID:19666503 Mouse Kif7 activity depends on the presence of cilia and Kif7-eGFP localizes to base of the primary cilium in the absence of Shh. PMID:24952464 Here we show that Kif7 localizes to the cilium tip, the site of microtubule plus ends, where it limits cilium length and controls cilium structure. |
| GO:0005929 cilium | IDA PMID:19592253 The mammalian Cos2 homolog Kif7 plays an essential role in m... | ACCEPT | Summary: Cilium localisation by immunofluorescence in Endoh-Yamagami et al., who showed that KIF7 accumulates at the distal tip of primary cilia and that the accumulation is Hh-dependent (PMID:19592253). Reason: Correct and core, and this row is the primary experimental source for the localisation rather than a restatement of it. The Hh-dependence reported here is what makes the localisation functionally meaningful: KIF7 is recruited to the tip as the pathway turns on, which is the step the Hedgehog module records for the KIF7 annoton. Supporting Evidence: PMID:19592253 We show that Kif7 accumulates at the distal tip of the primary cilia in a Hh-dependent manner. PMID:19592253 Using Kif7 knockout mice, we demonstrate that mouse Kif7, like its zebrafish and Drosophila homologs, plays a role in transducing the Hh signal. |
| GO:0005929 cilium | IEA GO_REF:0000120 | ACCEPT | Summary: Automated cilium assignment combining ARBA:ARBA00028353 and the UniProt subcellular-location keyword SL-0066, both of which trace back to the same experimental localisation. Reason: An electronic row that agrees with the experimental ones. It is redundant rather than wrong, and the SubCell mapping is faithful to the UniProt annotation it derives from (UniProt: "Cell projection, cilium"). No change needed. Supporting Evidence: file:human/KIF7/KIF7-uniprot.txt Cell projection, cilium PMID:19592253 We show that Kif7 accumulates at the distal tip of the primary cilia in a Hh-dependent manner. |
| GO:0007018 microtubule-based movement | IBA GO_REF:0000033 | MODIFY | Summary: Microtubule-based movement from the kinesin-superfamily PAINT node. KIF7 is immotile and is not required for intraflagellar transport, so the motility sense of this term does not apply; but KIF7 does act on microtubule dynamics, slowing growth and promoting catastrophe at plus ends (PMID:24952464, PMID:29351996). Reason: GO:0007018 is broad enough to be technically defensible - its definition admits "movement driven by polymerization or depolymerization of microtubules", and KIF7 does drive depolymerisation of axonemal plus ends. That is why MODIFY rather than REMOVE is right: the parent statement survives through a clause the PAINT node did not intend, while the reason the node placed the term here (processive transport) is false for this descendant. Replacing it with negative regulation of microtubule polymerization states what KIF7 actually does and removes the motor implication. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: FUNCTIONAL DIVERGENCE GRANULARITY MISMATCH Sources checked: PANTHER:PTN000648413 SUPPORTS SOURCE BUT NOT TARGET The node asserts movement in the transport sense. KIF7 satisfies the term only through its polymerisation/depolymerisation clause, so the precise child term is the correct annotation for this descendant. Proposed replacements: negative regulation of microtubule polymerization Supporting Evidence: PMID:24952464 Purified recombinant Kif7 binds the plus ends of growing microtubules in vitro, where it reduces the rate of microtubule growth and increases the frequency of microtubule catastrophe. PMID:24952464 In addition to promoting catastrophe, KIF7 decreased the rate of microtubule growth in a dose-dependent manner PMID:24952464 Kif7 is not required for normal intraflagellar transport or for trafficking of Hh pathway proteins into cilia. PMID:29351996 KIF4 and KIF21 motors are fast and processive, KIF7 and its Drosophila melanogaster homologue Costal2 (Cos2) are immotile, and KIF27 is slow and processive. |
| GO:0007018 microtubule-based movement | IEA GO_REF:0000002 | MODIFY | Summary: Microtubule-based movement inferred from the kinesin motor domain signatures IPR001752, IPR019821 and IPR027640. The domain is present and does act on microtubules, but not by generating transport. Reason: The same reasoning as for the IBA row, applied to a domain-based inference: the mapping is right that this protein has a microtubule-directed activity and wrong about what it is. Rather than delete a statement that remains true through the depolymerisation clause of the definition, replace it with the specific term that the purified-protein assays support. Proposed replacements: negative regulation of microtubule polymerization Supporting Evidence: PMID:24952464 Together, our in vitro analysis suggests that the plus-end-associated KIF7 promotes catastrophe and inhibits microtubule growth in an ATP-hydrolysis dependent manner. PMID:29351996 We suggest that evolutionarily selected sequence differences enable immotile KIF7 and Cos2 motors to function not as transporters but as microtubule-based tethers of signaling complexes. |
| GO:0008017 microtubule binding | IBA GO_REF:0000033 | ACCEPT | Summary: Microtubule binding from the kinesin-superfamily PAINT node. Directly confirmed for KIF7: purified recombinant protein binds microtubules, with specificity for growing plus ends (PMID:24952464, PMID:29351996). Reason: The one molecular-function assertion from this node that transfers to KIF7 intact, and it is the core activity. Note the unusual situation: microtubule binding is retained while the motor activity from the same node is not - Yue et al. specifically report that KIF7 has high affinity for microtubules and fails at the stepping cycle, not at binding. A more specific child term, GO:0051010 microtubule plus-end binding, is proposed on the motor-activity rows rather than here, so this row can stand as the general statement. Supporting Evidence: PMID:24952464 KIF7 can interact directly with microtubules but lacks detectable motility PMID:24952464 Purified recombinant Kif7 binds the plus ends of growing microtubules in vitro, where it reduces the rate of microtubule growth and increases the frequency of microtubule catastrophe. PMID:29351996 The mechanistic basis of immotile KIF7 behavior arises from an inability to release adenosine diphosphate in response to microtubule binding |
| GO:0008017 microtubule binding | IEA GO_REF:0000002 | ACCEPT | Summary: Microtubule binding inferred from the kinesin motor domain signature IPR001752. Agrees with the IBA row and with direct measurement on purified KIF7. Reason: A domain-based inference that happens to be exactly right for this protein, and one of the few InterPro consequences of the kinesin motor domain that KIF7 retains. Accepted as core. Supporting Evidence: PMID:24952464 KIF7 can interact directly with microtubules but lacks detectable motility PMID:24952464 Purified recombinant Kif7 binds the plus ends of growing microtubules in vitro, where it reduces the rate of microtubule growth and increases the frequency of microtubule catastrophe. |
| GO:0016887 ATP hydrolysis activity | IBA GO_REF:0000033 | ACCEPT | Summary: ATP hydrolysis activity from the kinesin PAINT node. Measured directly on purified KIF7: basal and microtubule-stimulated ATPase rates were determined by NADH-coupled assay, and the plus-end activity is ATP-hydrolysis dependent (PMID:29351996, PMID:24952464). Reason: Worth separating carefully from the motor-activity row, because the two fail and survive for the same reason. KIF7 hydrolyses ATP - weakly, with only about a fivefold microtubule stimulation rather than the large stimulation seen in transport kinesins - and that hydrolysis is what powers catastrophe promotion, since AMP-PNP abolishes the effect. What KIF7 has lost is the coupling of hydrolysis to stepping, not hydrolysis itself. The activity is therefore accepted, and is core: it is the energetic basis of the plus-end function. Supporting Evidence: PMID:29351996 For immotile KIF7, very little microtubule-dependent stimulation of ATPase activity was observed. PMID:29351996 The mechanistic basis of immotile KIF7 behavior arises from an inability to release adenosine diphosphate in response to microtubule binding PMID:24952464 Together, our in vitro analysis suggests that the plus-end-associated KIF7 promotes catastrophe and inhibits microtubule growth in an ATP-hydrolysis dependent manner. |
| GO:0030705 cytoskeleton-dependent intracellular transport | IBA GO_REF:0000033 | REMOVE | Summary: Cytoskeleton-dependent intracellular transport, propagated from the transport-kinesin node PTN009082057. He et al. tested this requirement directly in Kif7 mutant cilia and found it absent: intraflagellar transport rates are unchanged and Hh pathway proteins still enter the cilium (PMID:24952464). Reason: This is the one KIF7 annotation for which a published experiment is a direct negative. He et al. measured anterograde and retrograde IFT velocities in wild-type and Kif7 mutant cilia and found no significant difference, showed that Gli2 still reaches the cilium without KIF7, and concluded that KIF7 is not required for normal intraflagellar transport or for trafficking of Hh pathway proteins into cilia. Combined with the immotility of the purified protein, there is no sense in which KIF7 moves cargo along the cytoskeleton. What KIF7 does is position cargo that other motors have already delivered - which is captured by the adaptor-activity replacements proposed on the protein-binding rows, not by a transport term. Removal is the right call for an over-propagated phylogenetic inference that specific experiments contradict. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE ROLE CONFLATION PSEUDO OR SUBACTIVITY LOSS Sources checked: PANTHER:PTN009082057 SUPPORTS SOURCE BUT NOT TARGET Node covering the transport kinesins, whose members do move cargo along microtubules. KIF7 descends from it but is immotile, and the transport requirement was tested and excluded experimentally in Kif7 mutant cilia. Supporting Evidence: PMID:24952464 Kif7 is not required for normal intraflagellar transport or for trafficking of Hh pathway proteins into cilia. PMID:24952464 Thus there was no significant difference in the rates of IFT between wild type and Kif7L130P cilia, indicating that KIF7 does not control cilia length by affecting the rates of IFT. PMID:24952464 Thus KIF7 is not required for trafficking of Gli2 into cilia, but it does control proper localization of Gli2 within the cilium. PMID:29351996 We suggest that evolutionarily selected sequence differences enable immotile KIF7 and Cos2 motors to function not as transporters but as microtubule-based tethers of signaling complexes. |
| GO:0036064 ciliary basal body | ISS GO_REF:0000024 | ACCEPT | Summary: Ciliary basal body localisation transferred by curator judgment from mouse Kif7 (UniProtKB:B7ZNG0). The mouse evidence is direct: Kif7-eGFP sits at the base of the primary cilium in the absence of Shh and moves to the tip when the pathway is activated (PMID:19666503). Reason: A sound one-to-one orthologue transfer. Mouse and human KIF7 are unambiguous orthologues in the same PANTHER subfamily (PTHR24115:SF445), and the mouse record independently carries an experimental IDA for this same term. The basal-body pool is the resting state of the protein and complements the ciliary-tip rows, which report the activated state; together they describe the base-to-tip redistribution that is the hallmark of KIF7 behaviour. Accepted as core because the redistribution, not just the endpoint, is part of how the pathway is read out. Supporting Evidence: PMID:19666503 Mouse Kif7 activity depends on the presence of cilia and Kif7-eGFP localizes to base of the primary cilium in the absence of Shh. PMID:19666503 Activation of the Shh pathway promotes trafficking of Kif7-eGFP from the base to the tip of the cilium, and localization to the tip of the cilium is disrupted in a motor domain mutant. |
| GO:0045879 negative regulation of smoothened signaling pathway | ISS GO_REF:0000024 | ACCEPT | Summary: Negative regulation of the smoothened signaling pathway, transferred from mouse Kif7. Mouse Kif7 carries three independent IMP rows for this term, from three separate 2009 studies, and the phenotype is consistent across species: loss of Kif7 causes ectopic, ligand-independent pathway activity (PMID:19666503, PMID:19549984, PMID:19592253). Reason: Core, and mechanistically explained rather than merely observed. KIF7 restrains the pathway by confining GLI-SUFU complexes to a single ciliary tip compartment; when KIF7 is absent, those complexes appear in ectopic tip-like sites along the axoneme where they are inappropriately activated without ligand (PMID:24952464). The transfer from mouse is safe - same subfamily, same phenotype reported in zebrafish and in human patient tissue - and the negative arm is one of the two halves of KIF7 function that every study since 2009 has reproduced. Supporting Evidence: PMID:19666503 we show that, similar to Drosophila and zebrafish Cos2, mouse Kif7 acts downstream of Smo and upstream of Gli2 and has both negative and positive roles in Shh signal transduction PMID:19549984 Similar to Cos2, Kif7 physically interacted with Gli transcription factors and controlled their proteolysis and stability, and acted both positively and negatively in Hh signaling. PMID:24952464 Instead, a central function of Kif7 in the mammalian Hh pathway is to control cilium architecture and to create a single cilium tip compartment, where Gli-Sufu activity can be correctly regulated. PMID:24952464 We propose that the ectopic activation of the pathway seen in Kif7 mutants is due to the ectopic Gli/Sufu complexes away from the cilia tip, where they become inappropriately activated in the absence of ligand PMID:21552264 Consistent with a role of KIF7 in Hedgehog signaling, we show deregulation of most GLI transcription factor targets and impaired GLI3 processing in tissues from individuals with KIF7 mutations. |
| GO:0045880 positive regulation of smoothened signaling pathway | ISS GO_REF:0000024 | ACCEPT | Summary: Positive regulation of the smoothened signaling pathway, transferred from mouse Kif7, which carries two IMP rows for the term. The positive arm has been dissected genetically: it consists of relieving SUFU inhibition of GLI, and is separable from the negative arm (PMID:21795282, PMID:23034632). Reason: Core. The apparent paradox of one protein carrying both regulatory signs is resolved rather than unexplained here: KIF7 promotes signalling by driving SUFU turnover and SUFU-GLI dissociation, and halving the Sufu dose is sufficient to restore normal pathway output in Kif7-null mice - a genetic demonstration that the positive role is to restrict SUFU (PMID:21795282). The same Sufu-dependent positive function operates in keratinocytes (PMID:23034632) and in zebrafish (PMID:24339784). Endoh-Yamagami et al. describe the other positive contribution, preventing inappropriate GLI3 cleavage into the repressor form in the presence of ligand (PMID:19592253). This is the annotation that matches the Hedgehog module, where the KIF7 annoton serves both the off and the on state. Supporting Evidence: PMID:21795282 Importantly, halving the dose of Sufu restores normal hedgehog pathway activity and chondrocyte development in Kif7-null mice, demonstrating that the positive role of Kif7 is to restrict the inhibitory activity of Sufu. PMID:23034632 Kif7 possesses Sufu-dependent and -independent regulatory functions in Hh signaling: while it promotes Hh pathway activity through the dissociation of Sufu-Gli2 complex, it also contributes to the repression of Hh target genes in the absence of Sufu. PMID:24339784 We also show that zebrafish Kif7 potentiates Gli2a activity by promoting its dissociation from the Suppressor of Fused (Sufu) protein PMID:19592253 These results suggest a role for Kif7 in coordinating Hh signal transduction at the tip of cilia and preventing Gli3 cleavage into a repressor form in the presence of Hh. |
| GO:0097542 ciliary tip | IDA GO_REF:0000052 | ACCEPT | Summary: Ciliary tip localisation from curated immunofluorescence (HPA, GO_REF:0000052). This is the defining localisation of KIF7 and is reproduced in mouse, human and zebrafish cells (PMID:19592253, PMID:24952464, PMID:24339784). Reason: Core, and the single most informative component annotation KIF7 has. The tip is where the microtubule plus ends are, which is why a plus-end-binding protein ends up there (PMID:24952464), and it is where the GLI-SUFU complexes it regulates are enriched. Targeting is autonomous: KIF7 still reaches cilia tips in cells lacking Smo or Gli2 and Gli3. This is exactly the location the Hedgehog module assigns to the KIF7 ciliary-tip scaffold annoton. Supporting Evidence: PMID:19592253 We show that Kif7 accumulates at the distal tip of the primary cilia in a Hh-dependent manner. PMID:24952464 Here we show that Kif7 localizes to the cilium tip, the site of microtubule plus ends, where it limits cilium length and controls cilium structure. PMID:24952464 KIF7 was also present at cilia tips in MEFs derived from mutant embryos that lack Smo or Gli2 and Gli3, indicating that KIF7 is targeted to cilia independently of Shh pathway proteins |
| GO:0097542 ciliary tip | TAS Reactome:R-HSA-5610733 | ACCEPT | Summary: Ciliary tip localisation asserted by Reactome reaction R-HSA-5610733, "KIF7 is recruited to the ciliary tip through interaction with axonemal microtubules". The cached Reactome text is up to date with the primary literature and already describes KIF7 as binding axonemal microtubule plus ends and inhibiting their growth. Reason: A TAS row that duplicates the experimentally supported ciliary-tip annotation, and one whose author statement is accurate: Reactome names the mechanism of recruitment (interaction with axonemal microtubules) rather than assuming motor-driven delivery, and it credits He et al. for the ATP-dependent growth inhibition. Accepted as core alongside the IDA row. Worth noting that Reactome still calls KIF7 a "kinesin-4 motor protein" in the same sentence; that is family nomenclature rather than an activity claim, and the mechanism it then describes is the correct one. Supporting Evidence: Reactome:R-HSA-5610733 KIF7, the human ortholog of Drosophila COS2, is a kinesin-4 motor protein that binds directly to the plus ends of axonemal microtubules and inhibits their growth in an ATP-dependent manner Reactome:R-HSA-5610733 How KIF7 itself is localized to the cilia tip is unknown, although localization depends on the KIF7 motor domain |
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Download this section (compressed HTML)Q: KIF7 hydrolyses ATP and needs that hydrolysis to promote microtubule catastrophe, yet it cannot step. Is there a GO molecular function that captures a nucleotide-driven, non-translocating plus-end regulator, or does the ontology force such proteins to choose between "microtubule motor activity", which is false, and "microtubule plus-end binding", which omits the catalysis? This affects every immotile kinesin, not only KIF7.
Q: Does the single adaptor activity proposed here really account for both regulatory signs, or are the negative and positive arms separable at the level of KIF7 itself? Halving Sufu rescues the Kif7-null chondrocyte phenotype, which argues that the positive arm is entirely SUFU-directed, while the negative arm persists when Sufu is absent. A KIF7 separation-of-function allele would settle whether these are one activity read in two contexts or two activities.
Q: KIF7 homodimerises and mouse Kif7 carries an experimental identical-protein-binding annotation, but human KIF7 has no such row. Is dimerisation required for plus-end tracking, as it is for other kinesin-4 proteins, and if so should it be annotated for human KIF7 despite being another uninformative child of protein binding?
Q: Zebrafish Kif7 accumulates in cytoplasmic puncta that disperse on pathway activation, and Drosophila Costal-2 can substitute for Kif7 outright. Do mammalian cells retain a functional cytoplasmic KIF7-GLI complex of the Drosophila kind alongside the ciliary one, or is the cytoplasmic pool purely a staging reservoir? The answer decides whether cytoplasm deserves more than a non-core location for vertebrate KIF7.
Q: P4HA2 reaches the ciliary tip only via KIF7 and hydroxylates SUFU there. Is P4HA2 one of a wider set of modifying enzymes that KIF7 delivers to the tip, which would make "enzyme-delivery adaptor" the general description of KIF7 function, or is it a lineage- or tissue-specific addition to the pathway?
Experiment: Build KIF7 variants that separate the two activities: motor-domain point mutants that abolish microtubule binding but retain the GLI-binding region, and C-terminal truncations that retain plus-end tracking but lose GLI binding. Express each at endogenous level in KIF7-null cells and score, in parallel, plus-end tracking in vitro, cilium length and axonemal acetylation, the number of IFT81-positive tip-like compartments, and the distribution of GLI2 and SUFU along the axoneme. If tethering is downstream of plus-end binding, the motor-domain mutants should reproduce the full null phenotype while the C-terminal truncations should give normal cilium architecture with mislocalised GLI-SUFU.
Hypothesis: The GLI-SUFU tethering function of KIF7 is a consequence of plus-end binding and fails whenever KIF7 cannot reach or hold microtubule plus ends.
Type: structure-guided mutagenesis with paired in vitro and ciliary readouts
Experiment: Use an inducible degron on endogenous KIF7 in cells expressing tagged GLI2 and SUFU, and follow single complexes by live imaging through the first hour of KIF7 depletion. Measure entry frequency at the ciliary base, transit velocity, dwell time at the tip, and the appearance of ectopic dwell sites along the axoneme, alongside IFT particle velocities in the same cells. Transport models predict reduced entry and slowed transit; the tethering model predicts unchanged entry and transit with loss of tip dwell and new ectopic dwell sites.
Hypothesis: KIF7 positions GLI-SUFU complexes that other motors deliver, rather than transporting them, so acute loss of KIF7 should redistribute existing ciliary GLI without changing its rate of entry.
Type: acute degron depletion with single-particle live ciliary imaging
Experiment: Compare the ciliary-tip proteome of wild-type and KIF7-null cells before and after pathway activation, using tip-targeted proximity labelling rather than whole-cilium preparations so that ectopic tip-like compartments can be distinguished from the true tip. Cross-reference the KIF7-dependent set against the KIF7 GLI-binding-domain interactome and test the strongest candidates for SUFU or GLI modification in vitro. A set of modifying enzymes whose ciliary delivery requires KIF7 would generalise the P4HA2 result; a KIF7-dependent set limited to GLI, SUFU and P4HA2 would not.
Hypothesis: KIF7 is a general delivery adaptor for enzymes that modify the GLI-SUFU complex at the ciliary tip, of which P4HA2 is one example.
Type: compartment-resolved proximity labelling with targeted biochemical follow-up
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