Dihydropyrimidinase-related protein 5 (DPYSL5; also CRMP5, CRAM, DRP-5, ULIP-6), a brain-enriched cytoplasmic member of the collapsin response mediator protein (CRMP) / dihydropyrimidinase-related family. Although it is ~57% identical to dihydropyrimidinase and belongs to the metallo-dependent hydrolase (amidohydrolase) superfamily, DPYSL5 lacks the conserved metal-cofactor-binding residues required for catalysis and has no dihydropyrimidinase / amidohydrolase activity - it is a catalytically dead (pseudoenzyme) family member. Its function is as a cytoskeleton-associated regulator of neuronal morphogenesis: it negatively regulates dendrite/neurite outgrowth and is most highly expressed in fetal and neonatal brain, where it is up-regulated during neuronal differentiation. DPYSL5 forms homotetramers and heterotetramers with other CRMP-family proteins (notably DPYSL2/CRMP2) and associates with CRMP3 and protein-tyrosine kinases, acting within the semaphorin/collapsin growth-cone signalling system. Loss-of-function and dominant missense variants cause a neurodevelopmental disorder featuring agenesis of the corpus callosum and cerebellar abnormalities.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: DPYSL5/CRMP5 is a cytosolic protein (UniProt: Cytoplasm). is_active_in cytosol by phylogenetic inference is consistent with the CRMP family and with its role as a cytoskeleton-associated regulator. Reason: Correct localization. CRMPs are soluble cytoplasmic proteins; UniProt records DPYSL5 as cytoplasmic. Supporting Evidence: file:human/DPYSL5/DPYSL5-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0004157 dihydropyrimidinase activity | IBA NOT GO_REF:0000033 | ACCEPT | Summary: This is a NOT (negated) annotation: DPYSL5 does NOT enable dihydropyrimidinase activity. Although DPYSL5 belongs to the metallo-dependent hydrolase (dihydropyrimidinase/amidohydrolase) superfamily and is ~57% identical to dihydropyrimidinase, it lacks the conserved metal-cofactor-binding residues required for catalysis (UniProt CAUTION). Reason: The negation is correct and important. DPYSL5 is a catalytically dead family member; the curated NOT|enables faithfully encodes the loss of activity flagged by the UniProt CAUTION. Retain as-is. Supporting Evidence: file:human/DPYSL5/DPYSL5-uniprot.txt Lacks most of the conserved residues that are essential for binding the metal cofactor and hence for dihydropyrimidinase activity. |
| GO:0006208 pyrimidine nucleobase catabolic process | IBA NOT GO_REF:0000033 | ACCEPT | Summary: NOT (negated) annotation: DPYSL5 is NOT involved in pyrimidine nucleobase catabolism. This is the process counterpart of the absent dihydropyrimidinase activity. Reason: Correct negation, consistent with the loss of catalytic activity (no metal cofactor binding). Retain. Supporting Evidence: file:human/DPYSL5/DPYSL5-uniprot.txt Lacks most of the conserved residues that are essential for binding the metal cofactor and hence for dihydropyrimidinase activity. |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: Cytoplasmic localization by automated IEA, consistent with UniProt and with the IBA cytosol annotation. Reason: Correct, if broad, localization. CRMP5 is a cytoplasmic protein. Supporting Evidence: file:human/DPYSL5/DPYSL5-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0016787 hydrolase activity | IEA GO_REF:0000002 | REMOVE | Summary: Positive IEA 'hydrolase activity' propagated from the metallo-dependent hydrolase fold signature (InterPro IPR006680, Amidohydrolase-related). DPYSL5 belongs to this superfamily by sequence, but the UniProt CAUTION states it lacks the conserved metal-cofactor-binding residues 'essential for ... dihydropyrimidinase activity', and metallo-hydrolase catalysis across this superfamily depends on that metal centre. Reason: Domain-based electronic over-propagation that should be removed on biological grounds. The annotation rests solely on the fold signature; the catalytic prerequisite (metal-cofactor binding) is demonstrably absent, the curated GO:0004157 (dihydropyrimidinase) is itself NOT-ed, and there is no positive evidence DPYSL5 performs any hydrolysis. Its established function is non-catalytic (negative regulation of dendrite outgrowth). NB: this is not a logical contradiction with the NOT (GO NOT propagates to child terms, not up to parents) - it is an unsupported, biologically implausible over-annotation. A weaker action (MARK_AS_OVER_ANNOTATED) does not fit, since that is for terms the gene is genuinely related to but peripheral on; here the activity is absent. Supporting Evidence: file:human/DPYSL5/DPYSL5-uniprot.txt Lacks most of the conserved residues that are essential for binding the metal cofactor and hence for dihydropyrimidinase activity. file:human/DPYSL5/DPYSL5-uniprot.txt Belongs to the metallo-dependent hydrolases superfamily. |
| GO:0016810 hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds | IEA GO_REF:0000002 | REMOVE | Summary: Positive IEA 'hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds' propagated from the metallo-dependent hydrolase composite fold (InterPro IPR011059). Same basis and same problem as the GO:0016787 parent term. Reason: Domain-based over-propagation contradicted on biological grounds by the loss of metal-cofactor-binding residues (UniProt CAUTION). No positive evidence of any C-N hydrolase activity; curated dihydropyrimidinase activity is NOT-ed. Remove, consistent with the GO:0016787 removal. Supporting Evidence: file:human/DPYSL5/DPYSL5-uniprot.txt Lacks most of the conserved residues that are essential for binding the metal cofactor and hence for dihydropyrimidinase activity. file:human/DPYSL5/DPYSL5-uniprot.txt Belongs to the metallo-dependent hydrolases superfamily. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: IPI 'protein binding' annotation; the with/from partner is DPYSL2/CRMP2 (Q16555). DPYSL5 forms homo- and hetero-oligomers with other CRMP-family members, so this captures a real CRMP5-CRMP2 interaction. Reason: The interaction is biologically meaningful (CRMP hetero-oligomerization) but the generic 'protein binding' term is uninformative about molecular function (curation guideline). Keep as non-core supporting evidence for oligomerization rather than as a core function. Supporting Evidence: file:human/DPYSL5/DPYSL5-uniprot.txt Homotetramer, and heterotetramer with other DPYS-like proteins |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | KEEP AS NON CORE | Summary: IPI 'protein binding' annotation; the with/from partner is DPYSL2/CRMP2 (Q16555). DPYSL5 forms homo- and hetero-oligomers with other CRMP-family members, so this captures a real CRMP5-CRMP2 interaction. Reason: The interaction is biologically meaningful (CRMP hetero-oligomerization) but the generic 'protein binding' term is uninformative about molecular function (curation guideline). Keep as non-core supporting evidence for oligomerization rather than as a core function. Supporting Evidence: file:human/DPYSL5/DPYSL5-uniprot.txt Homotetramer, and heterotetramer with other DPYS-like proteins |
| GO:0005515 protein binding | IPI PMID:29892012 An interactome perturbation framework prioritizes damaging m... | KEEP AS NON CORE | Summary: IPI 'protein binding' annotation; the with/from partner is DPYSL2/CRMP2 (Q16555). DPYSL5 forms homo- and hetero-oligomers with other CRMP-family members, so this captures a real CRMP5-CRMP2 interaction. Reason: The interaction is biologically meaningful (CRMP hetero-oligomerization) but the generic 'protein binding' term is uninformative about molecular function (curation guideline). Keep as non-core supporting evidence for oligomerization rather than as a core function. Supporting Evidence: file:human/DPYSL5/DPYSL5-uniprot.txt Homotetramer, and heterotetramer with other DPYS-like proteins |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | KEEP AS NON CORE | Summary: IPI 'protein binding' annotation; the with/from partner is DPYSL2/CRMP2 (Q16555). DPYSL5 forms homo- and hetero-oligomers with other CRMP-family members, so this captures a real CRMP5-CRMP2 interaction. Reason: The interaction is biologically meaningful (CRMP hetero-oligomerization) but the generic 'protein binding' term is uninformative about molecular function (curation guideline). Keep as non-core supporting evidence for oligomerization rather than as a core function. Supporting Evidence: file:human/DPYSL5/DPYSL5-uniprot.txt Homotetramer, and heterotetramer with other DPYS-like proteins |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Generic 'protein binding' from a large-scale interactome screen. Uninformative about DPYSL5's molecular function. Reason: High-throughput interactome 'protein binding' carries no specific functional signal; per curation guidelines avoid 'protein binding' in favour of informative MF terms. Over-annotation. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MARK AS OVER ANNOTATED | Summary: Generic 'protein binding' from a large-scale interactome screen. Uninformative about DPYSL5's molecular function. Reason: High-throughput interactome 'protein binding' carries no specific functional signal; per curation guidelines avoid 'protein binding' in favour of informative MF terms. Over-annotation. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: IPI 'protein binding' annotation; the with/from partner is DPYSL2/CRMP2 (Q16555). DPYSL5 forms homo- and hetero-oligomers with other CRMP-family members, so this captures a real CRMP5-CRMP2 interaction. Reason: The interaction is biologically meaningful (CRMP hetero-oligomerization) but the generic 'protein binding' term is uninformative about molecular function (curation guideline). Keep as non-core supporting evidence for oligomerization rather than as a core function. Supporting Evidence: file:human/DPYSL5/DPYSL5-uniprot.txt Homotetramer, and heterotetramer with other DPYS-like proteins |
| GO:0030182 neuron differentiation | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Neuron differentiation (IEA). DPYSL5/CRAM is brain-specific, strongly up-regulated during neuronal differentiation and in fetal/neonatal brain. Reason: Correct but broad developmental process; non-core relative to the specific dendrite-morphogenesis role. Supporting Evidence: PMID:10851247 CRAM expression is up-regulated during neuronal differentiation of embryonal carcinoma P19 and PC12 cells |
| GO:0030425 dendrite | IEA GO_REF:0000107 | ACCEPT | Summary: Dendrite localization (IEA from ortholog transfer), consistent with CRMP5's role in regulating dendrite outgrowth/morphogenesis. Reason: Consistent with the cytoskeletal/dendritic function and with the IMP dendrite-morphogenesis annotation. Supporting Evidence: file:human/DPYSL5/DPYSL5-uniprot.txt FUNCTION: Involved in the negative regulation of dendrite outgrowth. |
| GO:0032991 protein-containing complex | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Part of a protein-containing complex (IEA). DPYSL5 forms homotetramers and heterotetramers with other DPYS-like (CRMP) proteins. Reason: Correct but very generic complex term; non-core. The specific oligomerization is better captured by the CRMP2 interaction evidence. Supporting Evidence: file:human/DPYSL5/DPYSL5-uniprot.txt Homotetramer, and heterotetramer with other DPYS-like proteins |
| GO:0043025 neuronal cell body | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Neuronal cell body localization (IEA from ortholog transfer). Reason: Plausible neuronal localization, consistent with brain-specific cytoplasmic expression; non-core. Supporting Evidence: file:human/DPYSL5/DPYSL5-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0045202 synapse | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Synapse (IEA from ortholog transfer). Reason: Broad neuronal localization; plausible but non-core and electronically inferred. |
| GO:0098978 glutamatergic synapse | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Glutamatergic synapse (IEA from ortholog transfer / SynGO-style mapping). Reason: Specific synaptic-type localization by electronic transfer; plausible but non-core, no direct experimental support in hand. |
| GO:0050774 negative regulation of dendrite morphogenesis | IMP PMID:33894126 Missense variants in DPYSL5 cause a neurodevelopmental disor... | ACCEPT | Summary: Negative regulation of dendrite morphogenesis (IMP). Jeanne et al. 2021 showed missense variants in DPYSL5 cause a neurodevelopmental disorder (corpus callosum agenesis, cerebellar abnormalities) and link DPYSL5 to control of dendrite/neurite outgrowth. Reason: Core function with direct mutational (IMP) evidence and matching the UniProt FUNCTION statement. This is the best-supported specific role of DPYSL5. Supporting Evidence: PMID:33894126 Missense variants in DPYSL5 cause a neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities. file:human/DPYSL5/DPYSL5-uniprot.txt FUNCTION: Involved in the negative regulation of dendrite outgrowth. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-399944 | ACCEPT | Summary: Cytosol localization (Reactome TAS, semaphorin/CRMP signalling reaction). Reason: Correct cytosolic localization, consistent with other location annotations. Supporting Evidence: file:human/DPYSL5/DPYSL5-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-399947 | ACCEPT | Summary: Cytosol localization (Reactome TAS). Reason: Correct cytosolic localization (duplicate-by-reaction of the same valid annotation). Supporting Evidence: file:human/DPYSL5/DPYSL5-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-399951 | ACCEPT | Summary: Cytosol localization (Reactome TAS). Reason: Correct cytosolic localization (duplicate-by-reaction of the same valid annotation). Supporting Evidence: file:human/DPYSL5/DPYSL5-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0007165 signal transduction | TAS PMID:10851247 Identification of CRAM, a novel unc-33 gene family protein t... | KEEP AS NON CORE | Summary: Signal transduction (TAS, Inatome et al. 2000). CRAM/CRMP5 associates with CRMP3 and protein-tyrosine kinase(s) in developing brain. Reason: Very broad process term; true in spirit (CRMP signalling) but uninformative and non-core. Supporting Evidence: PMID:10851247 a novel CRMP3-associated protein, designated CRAM ... associates with CRMP3 and protein-tyrosine kinase(s) in the developing rat brain |
| GO:0007399 nervous system development | TAS PMID:10851247 Identification of CRAM, a novel unc-33 gene family protein t... | KEEP AS NON CORE | Summary: Nervous system development (TAS). DPYSL5/CRAM is brain-specific and developmentally regulated. Reason: Correct but broad; non-core relative to the specific dendrite-morphogenesis role. Supporting Evidence: PMID:10851247 The expression of CRAM is brain-specific, is high in fetal and neonatal rat brain |
| GO:0007411 axon guidance | TAS PMID:10851247 Identification of CRAM, a novel unc-33 gene family protein t... | KEEP AS NON CORE | Summary: Axon guidance (TAS). The CRMP family transduces semaphorin-induced growth-cone collapse during neural development; CRAM/CRMP5 associates with CRMP3 in this context. Reason: Genuine CRMP-family process, but DPYSL5's distinguishing, experimentally supported role is negative regulation of dendrite morphogenesis; keep axon guidance as a valid non-core process. Supporting Evidence: PMID:10851247 Four members of collapsin response mediator proteins (CRMPs) are thought to be involved in the semaphorin-induced growth cone collapse during neural development |
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Download this section (compressed HTML)Q: Does DPYSL5/CRMP5 retain any residual or neofunctionalized enzymatic activity, or is it strictly a non-catalytic scaffold? The UniProt CAUTION asserts loss of dihydropyrimidinase activity, but no assay has excluded all hydrolase activities.
Q: What is the molecular mechanism by which DPYSL5 negatively regulates dendrite outgrowth - does it antagonize CRMP2 (DPYSL2) within hetero-oligomers, and is this mediated through microtubule dynamics?
Experiment: Express and purify recombinant DPYSL5 and assay a panel of amidohydrolase/C-N hydrolase substrates (including dihydropyrimidinase substrates) with and without divalent metal supplementation; compare to active DPYS as a positive control.
Hypothesis: DPYSL5 has no metallo-hydrolase activity of any kind, consistent with loss of the metal-binding site.
Experiment: Test dendrite outgrowth in neurons co-expressing DPYSL5 and CRMP2 variants that disrupt hetero-oligomerization, quantifying dendrite number/length.
Hypothesis: DPYSL5 negatively regulates dendrite outgrowth by antagonizing CRMP2 in hetero-oligomers.
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