Dihydropyrimidinase-related protein 3 (DPYSL3/CRMP4), a cytoplasmic CRMP-family protein required for class-3 semaphorin signaling and cytoskeletal remodeling. A pseudoenzyme with respect to the ancestral dihydropyrimidinase reaction, it lacks the conserved metal-cofactor residues and has no dihydropyrimidinase activity. DPYSL3 is distinguished by F-actin binding/bundling and filopodium regulation, binds filamin and chondroitin sulfate, and modulates neuron projection development, growth-cone dynamics and cell migration. It forms homo- and hetero-tetramers with other CRMPs.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: cytosol: a core subcellular location for DPYSL3 (cytoplasmic/cytoskeletal CRMP). Reason: Correct core localization for a cytoskeleton-associated cytoplasmic protein. |
| GO:0006208 pyrimidine nucleobase catabolic process | IBA NOT GO_REF:0000033 | ACCEPT | Summary: The curated NOT assertion for DPYSL3 concerns pyrimidine nucleobase catabolism specifically. Reason: Retain the curated phylogenetic negation for the ancestral pyrimidine-degradation pathway, consistent with loss of its dihydropyrimidinase reaction and the characterized cytoskeletal role. No alternative structural or cofactor contribution to pyrimidine catabolism was identified. This does not imply exclusion from all nucleic-acid metabolism or from processes performed noncatalytically. Supporting Evidence: file:human/DPYSL3/DPYSL3-uniprot.txt Lacks most of the conserved residues that are essential for |
| GO:0016812 hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in cyclic amides | IBA GO_REF:0000033 | REMOVE | Summary: DPYSL3 lacks the conserved catalytic apparatus for ancestral dihydropyrimidinase-type cyclic-amide hydrolysis. Reason: The target UniProt caution documents missing metal-cofactor ligands; the CRMP2 crystal structure and CRMP5 negative assay independently corroborate loss of this ancestral reaction in the CRMP subfamily. The OpenScientist report supplies residue-level comparisons, with direct-assay and paralog-inference limitations kept explicit. These data challenge retention of catalytic activity in this target, rather than the strength or number of phylogenetic donors. Propagation Review Root cause: PROPAGATION BAD Failure modes: PSEUDO OR SUBACTIVITY LOSS Sources checked: PANTHER:PTN000182670 SUPPORTS SOURCE BUT NOT TARGET Proximate IBA ancestral node verified in the cached GOA WITH/FROM field. Target-specific loss of the catalytic apparatus, documented in the cited primary/sequence evidence, challenges retention of this ancestral reaction. The full PAINT reconstruction was not independently repeated; extant donor count or target self-inclusion is not evidence against the annotation. Supporting Evidence: file:human/DPYSL3/DPYSL3-uniprot.txt Lacks most of the conserved residues that are essential for PMID:28044206 Although CRMP-2, and other CRMPs, belong to the dihydropyrimidinase family, they have lost the enzymatic active site. PMID:23373749 CRMP-5 does not have any detectable amidohydrolase activity. |
| GO:0004157 dihydropyrimidinase activity | IBA NOT GO_REF:0000033 | ACCEPT | Summary: NOT: DPYSL3 does not have dihydropyrimidinase activity. It belongs to the metallo-dependent hydrolase superfamily but lacks the conserved metal-cofactor-binding residues required for catalysis (UniProt CAUTION). Reason: Correct, important negation: a catalytically dead family member. Retain. Supporting Evidence: file:human/DPYSL3/DPYSL3-uniprot.txt Lacks most of the conserved residues that are essential for |
| GO:0051764 actin crosslink formation | IBA GO_REF:0000033 | ACCEPT | Summary: actin crosslink formation: a core neuronal/cytoskeletal process for the CRMP family (DPYSL3 acts in semaphorin-driven cytoskeleton remodeling and neurite/axon development). Reason: Core biological process for a CRMP-family cytoskeletal regulator. |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: cytoplasm: a core subcellular location for DPYSL3 (cytoplasmic/cytoskeletal CRMP). Reason: Correct core localization for a cytoskeleton-associated cytoplasmic protein. |
| GO:0016787 hydrolase activity | IEA GO_REF:0000002 | REMOVE | Summary: The broad catalytic mapping derives from a hydrolase domain whose ancestral active site has been lost. Reason: For this target the mapped InterPro hydrolase reaction is contradicted by loss of the dihydropyrimidinase metal center, and the reviewed evidence does not establish an alternative hydrolytic reaction. Remove this catalytic inference rather than generalizing a defunct enzyme activity. This is not a claim that all CRMP paralogs can never evolve another enzymatic activity. Supporting Evidence: file:human/DPYSL3/DPYSL3-uniprot.txt Lacks most of the conserved residues that are essential for PMID:28044206 Although CRMP-2, and other CRMPs, belong to the dihydropyrimidinase family, they have lost the enzymatic active site. PMID:23373749 CRMP-5 does not have any detectable amidohydrolase activity. |
| GO:0016810 hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds | IEA GO_REF:0000002 | REMOVE | Summary: The broad catalytic mapping derives from a hydrolase domain whose ancestral active site has been lost. Reason: For this target the mapped InterPro hydrolase reaction is contradicted by loss of the dihydropyrimidinase metal center, and the reviewed evidence does not establish an alternative hydrolytic reaction. Remove this catalytic inference rather than generalizing a defunct enzyme activity. This is not a claim that all CRMP paralogs can never evolve another enzymatic activity. Supporting Evidence: file:human/DPYSL3/DPYSL3-uniprot.txt Lacks most of the conserved residues that are essential for PMID:28044206 Although CRMP-2, and other CRMPs, belong to the dihydropyrimidinase family, they have lost the enzymatic active site. PMID:23373749 CRMP-5 does not have any detectable amidohydrolase activity. |
| GO:0030426 growth cone | IEA GO_REF:0000120 | ACCEPT | Summary: growth cone: a core subcellular location for DPYSL3 (cytoplasmic/cytoskeletal CRMP). Reason: Correct core localization for a cytoskeleton-associated cytoplasmic protein. |
| GO:0005515 protein binding | IPI PMID:21044950 Genome-wide YFP fluorescence complementation screen identifi... | REMOVE | Summary: The cited interaction evidence is retained as context, but the generic protein-binding term does not specify a molecular function. Reason: PMID:21044950 reports protein interactions. Remove this uninformative GO:0005515 assertion under the annotation-reviewer policy; this does not reject the interaction or infer that the experiment assayed the wrong gene. A specific molecular function is not inferred from an interaction screen alone. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: The cited interaction evidence is retained as context, but the generic protein-binding term does not specify a molecular function. Reason: PMID:28514442 reports protein interactions. Remove this uninformative GO:0005515 assertion under the annotation-reviewer policy; this does not reject the interaction or infer that the experiment assayed the wrong gene. A specific molecular function is not inferred from an interaction screen alone. |
| GO:0005515 protein binding | IPI PMID:29892012 An interactome perturbation framework prioritizes damaging m... | REMOVE | Summary: The cited interaction evidence is retained as context, but the generic protein-binding term does not specify a molecular function. Reason: PMID:29892012 reports protein interactions. Remove this uninformative GO:0005515 assertion under the annotation-reviewer policy; this does not reject the interaction or infer that the experiment assayed the wrong gene. A specific molecular function is not inferred from an interaction screen alone. |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | REMOVE | Summary: The cited interaction evidence is retained as context, but the generic protein-binding term does not specify a molecular function. Reason: PMID:31515488 reports protein interactions. Remove this uninformative GO:0005515 assertion under the annotation-reviewer policy; this does not reject the interaction or infer that the experiment assayed the wrong gene. A specific molecular function is not inferred from an interaction screen alone. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: The cited interaction evidence is retained as context, but the generic protein-binding term does not specify a molecular function. Reason: PMID:33961781 reports protein interactions. Remove this uninformative GO:0005515 assertion under the annotation-reviewer policy; this does not reject the interaction or infer that the experiment assayed the wrong gene. A specific molecular function is not inferred from an interaction screen alone. |
| GO:0005515 protein binding | IPI Q14195-2 PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: The cited interaction evidence is retained as context, but the generic protein-binding term does not specify a molecular function. Reason: PMID:25416956 reports protein interactions. Remove this uninformative GO:0005515 assertion under the annotation-reviewer policy; this does not reject the interaction or infer that the experiment assayed the wrong gene. A specific molecular function is not inferred from an interaction screen alone. |
| GO:0005515 protein binding | IPI Q14195-2 PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: The cited interaction evidence is retained as context, but the generic protein-binding term does not specify a molecular function. Reason: PMID:32296183 reports protein interactions. Remove this uninformative GO:0005515 assertion under the annotation-reviewer policy; this does not reject the interaction or infer that the experiment assayed the wrong gene. A specific molecular function is not inferred from an interaction screen alone. |
| GO:0005576 extracellular region | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: extracellular region: a secondary/broad or context-specific localization for DPYSL3. Reason: Plausible but non-core (broad term, division-/synapse-specific, or high-throughput proteomics). |
| GO:0005829 cytosol | IEA GO_REF:0000107 | ACCEPT | Summary: cytosol: a core subcellular location for DPYSL3 (cytoplasmic/cytoskeletal CRMP). Reason: Correct core localization for a cytoskeleton-associated cytoplasmic protein. |
| GO:0010976 positive regulation of neuron projection development | IEA GO_REF:0000107 | ACCEPT | Summary: positive regulation of neuron projection development: a core neuronal/cytoskeletal process for the CRMP family (DPYSL3 acts in semaphorin-driven cytoskeleton remodeling and neurite/axon development). Reason: Core biological process for a CRMP-family cytoskeletal regulator. |
| GO:0010977 negative regulation of neuron projection development | IEA GO_REF:0000107 | ACCEPT | Summary: negative regulation of neuron projection development: a core neuronal/cytoskeletal process for the CRMP family (DPYSL3 acts in semaphorin-driven cytoskeleton remodeling and neurite/axon development). Reason: Core biological process for a CRMP-family cytoskeletal regulator. |
| GO:0017124 SH3 domain binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: SH3 domain binding: a specific molecular interaction consistent with DPYSL3's cytoskeletal-adapter role. Reason: Real, specific binding; informative but secondary to the core cytoskeletal-regulation function. Non-core. |
| GO:0030027 lamellipodium | IEA GO_REF:0000107 | ACCEPT | Summary: lamellipodium: a core subcellular location for DPYSL3 (cytoplasmic/cytoskeletal CRMP). Reason: Correct core localization for a cytoskeleton-associated cytoplasmic protein. |
| GO:0030336 negative regulation of cell migration | IEA GO_REF:0000107 | ACCEPT | Summary: negative regulation of cell migration: a core neuronal/cytoskeletal process for the CRMP family (DPYSL3 acts in semaphorin-driven cytoskeleton remodeling and neurite/axon development). Reason: Core biological process for a CRMP-family cytoskeletal regulator. |
| GO:0031941 filamentous actin | IEA GO_REF:0000107 | ACCEPT | Summary: filamentous actin: a core subcellular location for DPYSL3 (cytoplasmic/cytoskeletal CRMP). Reason: Correct core localization for a cytoskeleton-associated cytoplasmic protein. |
| GO:0035374 chondroitin sulfate binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: chondroitin sulfate binding: a specific molecular interaction consistent with DPYSL3's cytoskeletal-adapter role. Reason: Real, specific binding; informative but secondary to the core cytoskeletal-regulation function. Non-core. |
| GO:0042802 identical protein binding | IEA GO_REF:0000107 | ACCEPT | Summary: Homomeric association is an established structural property of CRMP assemblies. Reason: CRMPs form homo- and heterotetramers, and oligomeric assembly is part of their core cytoskeletal signaling architecture. Identical protein binding specifies self-association and is not equivalent to uninformative generic protein binding. Retain the supported annotation without claiming that every tetramer is constitutively stable. Supporting Evidence: PMID:23373749 CRMPs exist as homo- and/or hetero-tetramers in vivo and participate in signaling transduction, cytoskeleton rearrangements, and endocytosis. |
| GO:0044297 cell body | IEA GO_REF:0000107 | ACCEPT | Summary: cell body: a core subcellular location for DPYSL3 (cytoplasmic/cytoskeletal CRMP). Reason: Correct core localization for a cytoskeleton-associated cytoplasmic protein. |
| GO:0045202 synapse | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: synapse: a secondary/broad or context-specific localization for DPYSL3. Reason: Plausible but non-core (broad term, division-/synapse-specific, or high-throughput proteomics). |
| GO:0048666 neuron development | IEA GO_REF:0000107 | ACCEPT | Summary: neuron development: a core neuronal/cytoskeletal process for the CRMP family (DPYSL3 acts in semaphorin-driven cytoskeleton remodeling and neurite/axon development). Reason: Core biological process for a CRMP-family cytoskeletal regulator. |
| GO:0051017 actin filament bundle assembly | IEA GO_REF:0000107 | ACCEPT | Summary: actin filament bundle assembly: a core neuronal/cytoskeletal process for the CRMP family (DPYSL3 acts in semaphorin-driven cytoskeleton remodeling and neurite/axon development). Reason: Core biological process for a CRMP-family cytoskeletal regulator. |
| GO:0051219 phosphoprotein binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: phosphoprotein binding: a specific molecular interaction consistent with DPYSL3's cytoskeletal-adapter role. Reason: Real, specific binding; informative but secondary to the core cytoskeletal-regulation function. Non-core. |
| GO:0051491 positive regulation of filopodium assembly | IEA GO_REF:0000107 | ACCEPT | Summary: positive regulation of filopodium assembly: a core neuronal/cytoskeletal process for the CRMP family (DPYSL3 acts in semaphorin-driven cytoskeleton remodeling and neurite/axon development). Reason: Core biological process for a CRMP-family cytoskeletal regulator. |
| GO:0051764 actin crosslink formation | IEA GO_REF:0000107 | ACCEPT | Summary: actin crosslink formation: a core neuronal/cytoskeletal process for the CRMP family (DPYSL3 acts in semaphorin-driven cytoskeleton remodeling and neurite/axon development). Reason: Core biological process for a CRMP-family cytoskeletal regulator. |
| GO:0070382 exocytic vesicle | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: exocytic vesicle: a secondary/broad or context-specific localization for DPYSL3. Reason: Plausible but non-core (broad term, division-/synapse-specific, or high-throughput proteomics). |
| GO:0042802 identical protein binding | ISS GO_REF:0000024 | ACCEPT | Summary: Homomeric association is an established structural property of CRMP assemblies. Reason: CRMPs form homo- and heterotetramers, and oligomeric assembly is part of their core cytoskeletal signaling architecture. Identical protein binding specifies self-association and is not equivalent to uninformative generic protein binding. Retain the supported annotation without claiming that every tetramer is constitutively stable. Supporting Evidence: PMID:23373749 CRMPs exist as homo- and/or hetero-tetramers in vivo and participate in signaling transduction, cytoskeleton rearrangements, and endocytosis. |
| GO:0031005 filamin binding | IPI PMID:25358863 Amino- and carboxyl-terminal domains of Filamin-A interact w... | ACCEPT | Summary: filamin binding: a specific molecular interaction consistent with DPYSL3's cytoskeletal-adapter role. Reason: Filamin binding is a specific, experimentally demonstrated interaction (PMID:25358863) central to this CRMP's cytoskeletal-adapter role; retained as the representative core binding molecular function. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-399951 | ACCEPT | Summary: cytosol: a core subcellular location for DPYSL3 (cytoplasmic/cytoskeletal CRMP). Reason: Correct core localization for a cytoskeleton-associated cytoplasmic protein. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-399944 | ACCEPT | Summary: cytosol: a core subcellular location for DPYSL3 (cytoplasmic/cytoskeletal CRMP). Reason: Correct core localization for a cytoskeleton-associated cytoplasmic protein. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-399947 | ACCEPT | Summary: cytosol: a core subcellular location for DPYSL3 (cytoplasmic/cytoskeletal CRMP). Reason: Correct core localization for a cytoskeleton-associated cytoplasmic protein. |
| GO:0005576 extracellular region | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: extracellular region: a secondary/broad or context-specific localization for DPYSL3. Reason: Plausible but non-core (broad term, division-/synapse-specific, or high-throughput proteomics). |
| GO:0005829 cytosol | ISS GO_REF:0000024 | ACCEPT | Summary: cytosol: a core subcellular location for DPYSL3 (cytoplasmic/cytoskeletal CRMP). Reason: Correct core localization for a cytoskeleton-associated cytoplasmic protein. |
| GO:0010976 positive regulation of neuron projection development | ISS GO_REF:0000024 | ACCEPT | Summary: positive regulation of neuron projection development: a core neuronal/cytoskeletal process for the CRMP family (DPYSL3 acts in semaphorin-driven cytoskeleton remodeling and neurite/axon development). Reason: Core biological process for a CRMP-family cytoskeletal regulator. |
| GO:0010977 negative regulation of neuron projection development | ISS GO_REF:0000024 | ACCEPT | Summary: negative regulation of neuron projection development: a core neuronal/cytoskeletal process for the CRMP family (DPYSL3 acts in semaphorin-driven cytoskeleton remodeling and neurite/axon development). Reason: Core biological process for a CRMP-family cytoskeletal regulator. |
| GO:0017124 SH3 domain binding | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: SH3 domain binding: a specific molecular interaction consistent with DPYSL3's cytoskeletal-adapter role. Reason: Real, specific binding; informative but secondary to the core cytoskeletal-regulation function. Non-core. |
| GO:0030027 lamellipodium | ISS GO_REF:0000024 | ACCEPT | Summary: lamellipodium: a core subcellular location for DPYSL3 (cytoplasmic/cytoskeletal CRMP). Reason: Correct core localization for a cytoskeleton-associated cytoplasmic protein. |
| GO:0030336 negative regulation of cell migration | ISS GO_REF:0000024 | ACCEPT | Summary: negative regulation of cell migration: a core neuronal/cytoskeletal process for the CRMP family (DPYSL3 acts in semaphorin-driven cytoskeleton remodeling and neurite/axon development). Reason: Core biological process for a CRMP-family cytoskeletal regulator. |
| GO:0030426 growth cone | ISS GO_REF:0000024 | ACCEPT | Summary: growth cone: a core subcellular location for DPYSL3 (cytoplasmic/cytoskeletal CRMP). Reason: Correct core localization for a cytoskeleton-associated cytoplasmic protein. |
| GO:0031941 filamentous actin | ISS GO_REF:0000024 | ACCEPT | Summary: filamentous actin: a core subcellular location for DPYSL3 (cytoplasmic/cytoskeletal CRMP). Reason: Correct core localization for a cytoskeleton-associated cytoplasmic protein. |
| GO:0035374 chondroitin sulfate binding | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: chondroitin sulfate binding: a specific molecular interaction consistent with DPYSL3's cytoskeletal-adapter role. Reason: Real, specific binding; informative but secondary to the core cytoskeletal-regulation function. Non-core. |
| GO:0044297 cell body | ISS GO_REF:0000024 | ACCEPT | Summary: cell body: a core subcellular location for DPYSL3 (cytoplasmic/cytoskeletal CRMP). Reason: Correct core localization for a cytoskeleton-associated cytoplasmic protein. |
| GO:0048678 response to axon injury | ISS GO_REF:0000024 | ACCEPT | Summary: response to axon injury: a core neuronal/cytoskeletal process for the CRMP family (DPYSL3 acts in semaphorin-driven cytoskeleton remodeling and neurite/axon development). Reason: Core biological process for a CRMP-family cytoskeletal regulator. |
| GO:0051017 actin filament bundle assembly | ISS GO_REF:0000024 | ACCEPT | Summary: actin filament bundle assembly: a core neuronal/cytoskeletal process for the CRMP family (DPYSL3 acts in semaphorin-driven cytoskeleton remodeling and neurite/axon development). Reason: Core biological process for a CRMP-family cytoskeletal regulator. |
| GO:0051491 positive regulation of filopodium assembly | ISS GO_REF:0000024 | ACCEPT | Summary: positive regulation of filopodium assembly: a core neuronal/cytoskeletal process for the CRMP family (DPYSL3 acts in semaphorin-driven cytoskeleton remodeling and neurite/axon development). Reason: Core biological process for a CRMP-family cytoskeletal regulator. |
| GO:0051764 actin crosslink formation | ISS GO_REF:0000024 | ACCEPT | Summary: actin crosslink formation: a core neuronal/cytoskeletal process for the CRMP family (DPYSL3 acts in semaphorin-driven cytoskeleton remodeling and neurite/axon development). Reason: Core biological process for a CRMP-family cytoskeletal regulator. |
| GO:0070382 exocytic vesicle | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: exocytic vesicle: a secondary/broad or context-specific localization for DPYSL3. Reason: Plausible but non-core (broad term, division-/synapse-specific, or high-throughput proteomics). |
| GO:0071345 cellular response to cytokine stimulus | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: cellular response to cytokine stimulus: a broader/secondary process for DPYSL3. Reason: Valid but non-core relative to the cytoskeletal-regulation function. |
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Download this section (compressed HTML)Q: How does CRMP4 (DPYSL3) coordinate F-actin bundling and filopodium dynamics, and is this actin role separable from the microtubule functions of its paralog CRMP2?
Experiment: Assay F-actin bundling and filopodium formation with wild-type vs actin-binding-deficient DPYSL3 in neurons, comparing to DPYSL2.
Hypothesis: DPYSL3 acts primarily through F-actin bundling rather than microtubules.
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