CDKL5 is a serine/threonine protein kinase with an N-terminal catalytic domain and a long regulatory C-terminal region. It phosphorylates cytoskeletal regulatory proteins and supports dendritic microtubule dynamics and excitatory postsynaptic organization. Human neuronal models link loss of CDKL5 to reduced substrate phosphorylation and abnormal synaptic structure. A nuclear pool participates in transcriptional repression near induced DNA breaks, while additional centrosomal, midbody and ciliary functions have been demonstrated in defined cell-culture contexts. Alternative C-terminal products differ in expression and regulation. Pathogenic variants cause CDKL5 deficiency disorder, characterized by early seizures and severe neurodevelopmental impairment.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001764 neuron migration | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Conserved neuronal migration role supported by rat perturbation and rescue. Reason: The D3ZG85 donor retains experimental PMID:20861382 support. Rat cortical electroporation showed delayed migration and rescue; this developmental outcome is retained as an ortholog inference, not a direct human migration assay or the defining catalytic function. |
| GO:0004672 protein kinase activity | IBA GO_REF:0000033 | MODIFY | Summary: Refine inherited protein kinase activity to the established Ser/Thr activity. Reason: The PAINT assertion is compatible with CDKL5 catalysis. Independent human substrate assays resolve Ser/Thr phosphorylation more precisely. This is a specificity refinement, not a claim that the ancestral node is misplaced or that its donor count is inadequate. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000623091 UNRESOLVED Original PAINT node retained. Historical node assertion was not independently reconstructed; the broad kinase function is supported and the proposed refinement rests on direct human biochemistry. PANTHER:PTN000756102 UNRESOLVED Original PAINT node retained. Historical node assertion was not independently reconstructed; the broad kinase function is supported and the proposed refinement rests on direct human biochemistry. Proposed replacements: protein serine/threonine kinase activity |
| GO:0004672 protein kinase activity | IDA PMID:16935860 Functional consequences of mutations in CDKL5, an X-linked g... | MODIFY | Summary: Refine the experimentally supported kinase activity. Reason: The authentic original abstract reports CDKL5 kinase assays and autophosphorylation; its full methods were not independently accessed. Human substrate and phosphoacceptor assays in PMID:30266825 independently justify the more specific Ser/Thr activity without requiring the older MeCP2 substrate mechanism. Proposed replacements: protein serine/threonine kinase activity |
| GO:0004672 protein kinase activity | IDA PMID:27466189 HDAC4: a key factor underlying brain developmental alteratio... | MODIFY | Summary: Retain kinase activity with a chemically specific replacement. Reason: The original abstract describes CDKL5-dependent HDAC4 phosphorylation in a mouse-centered study. Full source-specific methods were not accessed; the proposed Ser/Thr activity is independently established by direct human CDKL5 substrate assays. This does not elevate HDAC4 to a definitively established principal substrate. Proposed replacements: protein serine/threonine kinase activity |
| GO:0004672 protein kinase activity | IEA GO_REF:0000002 | MODIFY | Summary: Resolve the catalytic-domain inference to Ser/Thr kinase activity. Reason: The source InterPro kinase domain supports protein phosphorylation. Direct substrate chemistry supplies greater specificity than the domain-level parent term; the original InterPro assertion and source fields remain intact. Proposed replacements: protein serine/threonine kinase activity |
| GO:0004674 protein serine/threonine kinase activity | IDA PMID:30266825 Phosphoproteomic screening identifies physiological substrat... | ACCEPT | Summary: CDKL5 phosphorylates serine and threonine acceptors. Reason: Human CDKL5-dependent MAP1S and CEP131 serine phosphorylation is validated in cells and peptide assays. A Thr-substituted MAP1S peptide retained approximately 55% of the Ser-peptide activity. Ser/Thr is therefore supported; serine specificity is not exclusive. The re-expression experiments used the 1030-aa product. Supporting Evidence: PMID:30266825 changing this residue to Thr permits peptide phosphorylation |
| GO:0004674 protein serine/threonine kinase activity | IDA PMID:34605059 CDKL5 kinase controls transcription-coupled responses to DNA... | ACCEPT | Summary: Nuclear substrate phosphorylation corroborates the kinase activity. Reason: The study detects CDKL5-dependent ELOA Ser311 phosphorylation and uses WT/kinase-dead comparisons. The NLS-directed phosphoproteomic screen is an engineered context, while loss of endogenous ELOA phosphorylation after CDKL5 depletion/disruption independently supports nuclear kinase function. Supporting Evidence: PMID:34605059 CDKL5‐dependent phosphorylation of endogenous ELOA Ser311 |
| GO:0004674 protein serine/threonine kinase activity | ISS GO_REF:0000024 | ACCEPT | Summary: Retain the experimentally grounded mouse-to-human kinase inference. Reason: The supplied MGI donor maps to mouse Cdkl5/Q3UTQ8, whose current annotations include experimental kinase evidence from PMID:30266824 and PMID:22922712. Human biochemical evidence independently confirms this conserved catalytic activity; a propagated mouse row does not erase its experimental grounding. |
| GO:0004693 cyclin-dependent protein serine/threonine kinase activity | IEA GO_REF:0000003 | MODIFY | Summary: Remove the unestablished cyclin requirement from the activity description. Reason: GO:0004693 and EC:2.7.11.22 require cyclin-dependent catalysis. Human CDKL structures and activity studies do not establish an activating cyclin and reveal divergence in the putative interface. Direct Ser/Thr catalysis is established, so retain that activity without claiming that no cyclin or other activating partner could ever bind. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: EC:2.7.11.22 SUPPORTS SOURCE BUT NOT TARGET Official EC definition requires activating cyclin association. The mapping faithfully imports that requirement, but inspected CDKL5 studies establish Ser/Thr catalysis without establishing this dependency. Proposed replacements: protein serine/threonine kinase activity |
| GO:0005515 protein binding | IPI PMID:21653829 Protein interactome reveals converging molecular pathways am... | UNDECIDED | Summary: The 2011 CDKL5–MLH1 screen assertion remains source-specifically unresolved. Reason: The full main article describes stringent human-library yeast two-hybrid screening, but its exact CDKL5–P40692 target row and construct boundaries in Table S2 were not recovered. The current bounded IntAct query contains no matching 2011 record. Later HuRI records independently corroborate this pair but do not establish the original screen result or validation subtype. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | KEEP AS NON CORE | Summary: Retain the exact reported CDKL5–SERPINB8 association. Reason: IntAct EBI-21766676 is a positive O76039–P50452 record from this paper: C-terminally tagged CDKL5 bait, anti-tag coimmunoprecipitation in human HEK293T cells, with a spoke-expanded association. This does not establish a purified binary interaction, substrate relation or transfer of the partner function. Supported generic binding is retained under the project policy. Supporting Evidence: file:human/CDKL5/CDKL5-source-evidence.json "interaction_id": "intact:EBI-21766676|imex:IM-25778-9519" |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the exact HuRI CDKL5–MLH1 pair. Reason: Three positive O76039–P40692 records (EBI-24279294, EBI-22320445, EBI-22778941) include validated, prey-pooling and array two-hybrid evidence in yeast hosts with human participants. Assay fusion tags are recorded in the accompanying extract. This supports binding without conferring DNA mismatch-repair activity on CDKL5. Supporting Evidence: file:human/CDKL5/CDKL5-source-evidence.json "interaction_id": "intact:EBI-24279294|imex:IM-25472-111363" file:human/CDKL5/CDKL5-source-evidence.json "interaction_id": "intact:EBI-22320445|imex:IM-25472-546" file:human/CDKL5/CDKL5-source-evidence.json "interaction_id": "intact:EBI-22778941|imex:IM-25472-25580" |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the exact HuRI CDKL5–GOLGA2 pair. Reason: Three positive O76039–Q08379 records (EBI-22737160, EBI-24261382, EBI-22731357) describe human participants in yeast two-hybrid assays. The recorded 13–1002 binding-region feature belongs to GOLGA2, not CDKL5. The interaction does not establish a Golgi-specific molecular function for CDKL5. Supporting Evidence: file:human/CDKL5/CDKL5-source-evidence.json "interaction_id": "intact:EBI-22737160|imex:IM-25472-23240" file:human/CDKL5/CDKL5-source-evidence.json "interaction_id": "intact:EBI-24261382|imex:IM-25472-109790" file:human/CDKL5/CDKL5-source-evidence.json "interaction_id": "intact:EBI-22731357|imex:IM-25472-22917" |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: Retain the exact BioPlex CDKL5–SERPINB8 association. Reason: IntAct EBI-54773445 records the positive O76039–P50452 association from anti-tag coimmunoprecipitation in HEK293T cells with C-terminally tagged CDKL5 bait. The spoke-expanded complex evidence supports generic association, not an independently verified direct interface or protease-regulatory function. Supporting Evidence: file:human/CDKL5/CDKL5-source-evidence.json "interaction_id": "intact:EBI-54773445|imex:IM-29278-13709" |
| GO:0005524 ATP binding | IDA PMID:16935860 Functional consequences of mutations in CDKL5, an X-linked g... | ACCEPT | Summary: ATP is the phosphate donor for CDKL5 catalysis. Reason: The original abstract reports ATP-dependent kinase assays rather than an affinity measurement. Independent radiolabeled-ATP and analog-sensitive CDKL5 experiments directly require nucleotide binding for catalysis. Retain the molecular activity without asserting an ATP dissociation constant. |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: The ATP-binding-domain inference agrees with direct kinase assays. Reason: The InterPro kinase/ATP-binding sites are consistent with the experimentally demonstrated use of ATP by human CDKL5. This is part of the catalytic core and not an inference of a separate ATPase function. |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: Nuclear activity is supported in a conditional DNA-damage response. Reason: Independent CDKL5 depletion/disruption reduces endogenous ELOA Ser311 phosphorylation at DNA-damage tracks, and WT but not kinase-dead CDKL5 restores DSB-induced transcriptional repression. This establishes nuclear catalytic function in the human cultured-cell damage context represented by the second core, beyond localization alone. The PAINT assertion and its source fields are preserved; historical ancestral-node reconstruction was not independently retrieved. The two observed outcomes do not establish ELOA Ser311 as the causal mediator of repression. |
| GO:0005634 nucleus | IDA PMID:16935860 Functional consequences of mutations in CDKL5, an X-linked g... | KEEP AS NON CORE | Summary: Retain experimentally described nuclear localization. Reason: The original abstract describes regulated nuclear entry and retention; full original localization methods were not accessed. Independent human nuclear recruitment, substrate phosphorylation and transcriptional-response assays corroborate the localization in a conditional nuclear function. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Retain the nuclear subcellular-location mapping. Reason: The UniProt location inference is consistent with human nuclear CDKL5 activity and recruitment experiments. This location is retained for the conditional nuclear role rather than being treated as proof that all protein products are constitutively nuclear. |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: Retain HPA-supported nucleoplasmic localization. Reason: The current HPA record for ENSG00000008086 identifies nucleoplasm as the main ICC/IF location with supported reliability. The result corroborates a nuclear pool but does not define its kinase substrate or resolve splice-product-specific localization. |
| GO:0005813 centrosome | IDA PMID:28740074 CDKL5 localizes at the centrosome and midbody and is require... | KEEP AS NON CORE | Summary: Endogenous human CDKL5 localizes to centrosomes. Reason: HeLa and MRC-5 staining, silencing controls and centrosomal fractionation support this localization. The same paper also studies other species; its human endogenous evidence is distinguished from those experiments. The centrosomal pool is retained outside the principal neuronal core. Supporting Evidence: |
| GO:0005813 centrosome | IDA PMID:29420175 CDKL Family Kinases Have Evolved Distinct Structural Feature... | KEEP AS NON CORE | Summary: Retain centrosomal localization of tagged human CDKL5. Reason: GFP-CDKL5 localized to centrosomes in non-ciliated human RPE-1 cells. This is an expressed human construct, not a native loss-of-function assay. Independent endogenous human evidence in PMID:28740074 corroborates the compartment. |
| GO:0005813 centrosome | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Retain the centrosome location mapping. Reason: The UniProt cellular-location inference agrees with endogenous HeLa/MRC-5 localization and expressed human RPE-1 CDKL5. These sources support a context-dependent centrosomal pool. |
| GO:0007052 mitotic spindle organization | IDA PMID:28740074 CDKL5 localizes at the centrosome and midbody and is require... | KEEP AS NON CORE | Summary: Retain the experimentally linked mitotic spindle phenotype with its mechanism bounded. Reason: Human HeLa/MRC-5 CDKL5 depletion causes multipolar spindles; murine siRNA-resistant CDKL5 rescues the HeLa phenotype. The study traces centrosome accumulation and cytokinesis defects, with H2B-S14D rescue and disrupted HIPK2 recruitment. It does not establish CDKL5 as a spindle structural component or microtubule nucleator. Retain this cell-division context outside the neuronal core. Supporting Evidence: |
| GO:0016301 kinase activity | IDA PMID:15917271 CDKL5 belongs to the same molecular pathway of MeCP2 and it ... | MODIFY | Summary: Refine the broad kinase annotation to established protein Ser/Thr catalysis. Reason: The original abstract reports autophosphorylation and mediated MeCP2 phosphorylation. Modern human substrate assays supply the more specific activity independently; this refinement does not require that MeCP2 is a principal physiological CDKL5 substrate. Proposed replacements: protein serine/threonine kinase activity |
| GO:0030425 dendrite | ISS GO_REF:0000024 | ACCEPT | Summary: CDKL5 acts in dendrites to phosphorylate cytoskeletal regulatory substrates. Reason: The MGI donor maps to mouse Cdkl5/Q3UTQ8 with experimental PMID:30266824 evidence. Neuronal knockout and phosphospecific substrate staining support dendritic kinase activity, and human patient-derived neurons show reduced EB2 phosphorylation. This supports active dendritic function, beyond the observation of localization alone. |
| GO:0030496 midbody | IDA PMID:28740074 CDKL5 localizes at the centrosome and midbody and is require... | KEEP AS NON CORE | Summary: Retain the endogenous human midbody localization. Reason: The paper follows endogenous CDKL5 from mitotic poles to midzone and midbody in HeLa cells, with additional localization controls. This contextual cytokinesis-associated pool is distinct from the neuronal dendritic core. Supporting Evidence: |
| GO:0031110 regulation of microtubule polymerization or depolymerization | ISS GO_REF:0000024 | ACCEPT | Summary: CDKL5 phosphorylation regulates neuronal microtubule dynamics. Reason: The experimentally grounded mouse donor is supported by altered EB3-positive microtubule growth after Cdkl5 loss, MAP1S knockdown rescue and phosphorylation-dependent MAP1S microtubule binding. Biochemical substrate experiments include human engineered CDKL5 and rodent proteins; patient-derived human neurons independently show reduced EB2 phosphorylation. Supporting Evidence: GO_REF:0000024 PMID:30266824 microtubules have longer EB3-labelled plus-end growth duration |
| GO:0031267 small GTPase binding | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Retain the Rac1-associated binding inference without assigning a GTPase regulator activity. Reason: The rat D3ZG85 donor carries PMID:20861382 IPI support with Rac1/Q6RUV5. Its rat CDKL5 C-terminal fragment pulls Rac1 from cell lysate, and full-length proteins associate in neuronal contexts. This supports a protein complex rather than a purified binary interface. It establishes neither Rac guanine-nucleotide exchange nor GTPase-activating activity. |
| GO:0032587 ruffle membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Retain stimulated membrane-ruffle colocalization as asserted. Reason: The source paper observes CDKL5/Rac1 enrichment at PDGF-induced fibroblast ruffles and rat-construct recruitment in COS-7 cells. Preserve the original colocalizes_with qualifier: this does not make CDKL5 an integral membrane protein or establish a human constitutive ruffle pool. |
| GO:0032839 dendrite cytoplasm | ISS GO_REF:0000024 | ACCEPT | Summary: A dendritic cytoplasmic kinase pool is central to neuronal function. Reason: Rat neuronal localization/fractionation and cytoplasm-restricted rescue support this donor localization. Independent microtubule-substrate evidence places functional CDKL5 signaling in dendrites, with human patient-derived neuronal corroboration. Supporting Evidence: GO_REF:0000024 PMID:20861382 CDKL5 regulated dendrite development through a cytoplasmic mechanism |
| GO:0034244 negative regulation of transcription elongation by RNA polymerase II | IDA PMID:34605059 CDKL5 kinase controls transcription-coupled responses to DNA... | MODIFY | Summary: Retain damage-associated RNAPII repression while leaving its inhibited stage unresolved. Reason: Human U2OS assays establish CDKL5-dependent repression after DNA breaks, with WT but not K42R rescue. The elongation model has real support: ELOA is an elongation factor and RNAPII-directed E3-ligase component, CDKL5 phosphorylates ELOA Ser311, and DRB blocks recruitment of both proteins. Earlier ATM/DNA-PK studies establish elongating-RNAPII responses to breaks. However, these findings do not identify the CDKL5-regulated step: DRB tests recruitment, ELOA recruitment persists without Ser311 phosphorylation, and the Discussion leaves the effect of this phosphorylation on ELOA function and repression open. The MS2 silencing Methods induce FokI for 3 h before adding doxycycline; the separate recruitment protocol activates transcription first. Endogenous SLCO5A1/RYR2 RNA measurements establish repression but not its stage. Therefore propose GO:0000122 for the demonstrated RNAPII inhibition without rejecting the plausible elongation mechanism. Live QuickGO closure excludes GO:0000122 from GO:0034244 ancestors: this is an intentional lateral replacement of narrower mechanistic wording, not a formal parent move. Proposed replacements: negative regulation of transcription by RNA polymerase II Supporting Evidence: PMID:34605059 CDKL5 facilitates the transcriptional silencing of genes at or close to DSB |
| GO:0035022 positive regulation of Rac protein signal transduction | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Retain CDKL5-dependent enhancement of Rac signaling in neuronal development. Reason: The rat source measures BDNF-induced Rac1 activation and uses Rac1 expression and dominant-negative epistasis with CDKL5 perturbation. The regulatory pathway is supported without attributing Rac exchange chemistry or a direct Rac phosphorylation event to CDKL5. |
| GO:0035861 site of double-strand break | IDA PMID:34605059 CDKL5 kinase controls transcription-coupled responses to DNA... | KEEP AS NON CORE | Summary: Retain recruitment to induced DNA double-strand-break sites. Reason: GFP-CDKL5 recruitment was studied with microirradiation and engineered FokI breaks. The specific FokI imaging used NLS-tagged CDKL5 with PARG/ATM inhibitor conditions and a low recruited-cell fraction. Endogenous substrate-phosphorylation and repression assays corroborate a nuclear damage-response role but do not convert the imaging into an untagged native localization experiment. Supporting Evidence: |
| GO:0036064 ciliary basal body | IDA PMID:29420175 CDKL Family Kinases Have Evolved Distinct Structural Feature... | KEEP AS NON CORE | Summary: Retain basal-body localization of expressed human CDKL5. Reason: GFP-tagged human CDKL5 colocalized with basal-body/ciliary markers in serum-starved RPE-1 cells. The localization is supported within that expressed-construct setting; physiological native ciliary activity and product equivalence are not established by this image alone. Supporting Evidence: |
| GO:0043197 dendritic spine | ISS GO_REF:0000024 | ACCEPT | Summary: CDKL5 acts in dendritic spines to support postsynaptic organization. Reason: The mouse donor has experimental PMID:22922712 support. Postsynaptic localization, CDKL5 silencing/kinase-dead phenotypes and human patient-derived neuronal spine abnormalities connect this compartment to function, rather than relying on staining alone. |
| GO:0044294 dendritic growth cone | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Retain the developing-neuron growth-cone location. Reason: The rat donor is supported by immunostaining and biochemical enrichment of CDKL5 in growth-cone preparations. This is a developmental compartment and does not imply that the kinase is an axon guidance receptor. |
| GO:0045773 positive regulation of axon extension | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Retain the positive axon-extension developmental inference. Reason: Rat neuronal CDKL5 depletion and overexpression alter neurite/axon growth, with rescue experiments in the inspected source. Retain the curator-selected developmental process as ortholog evidence without describing it as a direct human axonal assay or a distinct catalytic function. |
| GO:0050773 regulation of dendrite development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Retain regulation of dendritic development as a downstream neuronal role. Reason: The rat donor has direct perturbation/rescue evidence for dendritic length and branching. Conserved human neuronal abnormalities corroborate relevance, while the biochemical core is substrate phosphorylation and cytoskeletal/postsynaptic regulation. |
| GO:0050775 positive regulation of dendrite morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Retain the positive dendritic-morphogenesis direction from the rat source. Reason: Loss and gain of CDKL5 function produced opposing dendritic growth phenotypes and RNAi-resistant rescue in the source model. The direction is supported within this developmental setting, not asserted for every maturation stage or every human splice product. |
| GO:0050804 modulation of chemical synaptic transmission | IDA PMID:22922712 CDKL5 ensures excitatory synapse stability by reinforcing NG... | KEEP AS NON CORE | Summary: Retain modulation of excitatory synaptic activity as a physiological consequence. Reason: The paper measures decreased miniature excitatory postsynaptic currents after CDKL5 silencing in mouse hippocampal neurons, alongside altered synapse structure. Human patient-derived neurons supply structural corroboration, not a human patch-clamp experiment in this paper. The effect is retained outside the primary catalytic/organization description. Supporting Evidence: |
| GO:0050804 modulation of chemical synaptic transmission | IMP PMID:22922712 CDKL5 ensures excitatory synapse stability by reinforcing NG... | KEEP AS NON CORE | Summary: Retain the perturbation-supported synaptic transmission role. Reason: CDKL5 knockdown changes mouse hippocampal mEPSCs together with reduced excitatory contacts. The evidence supports modulation without assigning CDKL5 transmitter release, receptor conductance or direct channel activity; the human arm documents spine/contact abnormalities. Supporting Evidence: |
| GO:0051726 regulation of cell cycle | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: Cell-cycle regulation has independent target evidence despite the over-specific MF premise. Reason: The GO_REF:0000108 assertion follows the cyclin-dependent kinase ontology link, whose cyclin requirement is refined to measured Ser/Thr kinase activity. Independently, PMID:28740074 measures longer prometaphase/cytokinesis, abnormal centrosome accumulation and division defects after human CDKL5 depletion. Thus retain the broad process in this proliferating-cell context, without relying solely on kinase-family naming. The preserved GO_REF:0000108 transfer premise becomes stale once GO:0004693 is refined; the contextual process is retained on independent experimental evidence, not as validation of that original inference. Re-curation from the experimental source would make this distinction explicit. |
| GO:0097542 ciliary tip | IDA PMID:29420175 CDKL Family Kinases Have Evolved Distinct Structural Feature... | KEEP AS NON CORE | Summary: Retain ciliary-tip localization of expressed human CDKL5. Reason: The RPE-1 experiments show GFP-CDKL5 at ciliary tips as well as basal bodies. This is a context-specific localization from human constructs, distinct from the C. elegans CDKL-1 transition-zone experiments and not proof of a native human tip-specific catalytic mechanism. Supporting Evidence: |
| GO:0098978 glutamatergic synapse | IDA PMID:22922712 CDKL5 ensures excitatory synapse stability by reinforcing NG... | ACCEPT | Summary: CDKL5 has a functional postsynaptic pool at glutamatergic synapses. Reason: Mouse postsynaptic fractionation/staining and perturbation support excitatory synapse function; human patient-derived neurons show CDKL5 spine enrichment and altered glutamatergic contacts. Retain the active-location claim with these species and assay scopes preserved. Supporting Evidence: PMID:22922712 CDKL5 localization at excitatory synapses |
| GO:0098978 glutamatergic synapse | IMP PMID:22922712 CDKL5 ensures excitatory synapse stability by reinforcing NG... | ACCEPT | Summary: Retain the functionally supported glutamatergic-synapse location. Reason: The perturbation data link CDKL5 loss to excitatory synapse abnormalities, and human neuronal imaging corroborates this compartment. The annotation is not interpreted as intrinsic glutamate receptor activity. Supporting Evidence: |
| GO:0099175 regulation of postsynapse organization | IDA PMID:22922712 CDKL5 ensures excitatory synapse stability by reinforcing NG... | ACCEPT | Summary: Postsynaptic organization is a central neuronal CDKL5 function. Reason: Silencing or kinase-dead expression disrupts spine structure, and RNAi-resistant rescue supports specificity. NGL-1/PSD95 association and phosphomutant assays suggest a route to organization, while human patient-derived neurons corroborate the structural phenotype. The exact biochemical substrate hierarchy remains incompletely resolved. Supporting Evidence: PMID:22922712 correct dendritic spine structure |
| GO:0099175 regulation of postsynapse organization | IMP PMID:22922712 CDKL5 ensures excitatory synapse stability by reinforcing NG... | ACCEPT | Summary: Retain perturbation evidence for postsynapse organization. Reason: The source shows CDKL5-dependent spine and excitatory-contact organization with neuronal rescue and patient-derived human phenotypes. This supports a regulatory kinase role, without claiming that CDKL5 itself is the synaptic adhesion bridge. Supporting Evidence: PMID:22922712 rescue both, normal spine morphology and density |
| GO:0106310 protein serine kinase activity | IEA GO_REF:0000116 | ACCEPT | Summary: Protein serine phosphorylation is directly established. Reason: The Rhea-mapped serine reaction agrees with cellular MAP1S/CEP131 sites and direct substrate assays. Positive Thr-substituted peptide phosphorylation independently supports the Ser/Thr activity. The two measured activities are biologically compatible; the current QuickGO is_a closure does not make GO:0106310 a descendant of GO:0004674, so compatibility is not based on an asserted parent/child relation. |
| GO:1902017 regulation of cilium assembly | IMP PMID:29420175 CDKL Family Kinases Have Evolved Distinct Structural Feature... | KEEP AS NON CORE | Summary: Retain regulation of cilium assembly in the tested expression context. Reason: Overexpressed human GFP-CDKL5 reduces the proportion of ciliated RPE-1 cells, with RNAi reversal of the overexpression phenotype. This supports a regulatory effect but not native human CDKL5 necessity for ciliogenesis. Worm CDKL-1 length phenotypes are not substituted for that missing experiment. Supporting Evidence: |
| GO:1904891 positive regulation of excitatory synapse assembly | ISS GO_REF:0000024 | ACCEPT | Summary: Retain a kinase-associated role in excitatory synapse assembly. Reason: The mouse MGI donor maps to experimental PMID:22922712 evidence, with CDKL5-dependent synaptic contacts, spine rescue and NGL-1 phosphomutant effects. Human patient-derived neuronal contact abnormalities corroborate conservation. This is regulatory participation rather than CDKL5 acting as an adhesion molecule. |
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Download this section (compressed HTML)Q: Which native human CDKL5 substrates causally connect kinase activity to postsynaptic organization, and how much of NGL-1/HDAC4 regulation is direct versus mediated through associated enzymes?
Q: How do the preserved 960-aa O76039-2 and 1030-aa O76039-1 products differ in localization and substrate control in human neurons? Primary transcript nomenclature and UniProt product numbers are not interchangeable.
Q: Which CDKL5-dependent substrate controls transcriptional repression near DNA breaks, and does the regulated step involve initiation, elongation or another transcriptional event?
Q: Does endogenous human CDKL5 control ciliogenesis at physiological levels, and which substrate explains the overexpression phenotype?
Q: What exact Table S2 construct/pair record underlies the PMID:21653829 CDKL5–MLH1 annotation? Later HuRI evidence supports the pair but does not resolve the original assay record.
Q: Can the GO:0051726 cell-cycle assertion be re-curated directly from PMID:28740074, replacing the stale GO_REF:0000108 inference from the unestablished cyclin-dependent kinase activity while preserving the original source history?
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