Dihydropyrimidinase-related protein 2 (DPYSL2/CRMP2), a brain-enriched cytoplasmic protein of the collapsin-response-mediator (CRMP) / dihydropyrimidinase family. Although it belongs to the metallo-dependent hydrolase superfamily, it lacks the conserved metal-cofactor-binding residues and has no dihydropyrimidinase activity - it is a pseudoenzyme with respect to this ancestral reaction. CRMP2 is a key cytoskeletal regulator in semaphorin-3A signaling: it binds tubulin heterodimers to promote microtubule assembly and axon specification/growth, mediates growth-cone collapse and neuronal polarity, and is inactivated by GSK3B/CDK5/ROCK phosphorylation. It forms homo- and hetero-tetramers with other CRMPs and also participates in vesicle/endocytic trafficking.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: cytosol: a core subcellular location for DPYSL2 (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 DPYSL2 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/DPYSL2/DPYSL2-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: DPYSL2 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/DPYSL2/DPYSL2-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. file:human/DPYSL2/DPYSL2-hypotheses/function-hypothesis-go-0016812/openscientist.md The single most decisive change is the **carboxylated lysine → leucine** substitution. |
| GO:0004157 dihydropyrimidinase activity | IBA NOT GO_REF:0000033 | ACCEPT | Summary: NOT: DPYSL2 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/DPYSL2/DPYSL2-uniprot.txt Lacks most of the conserved residues that are essential for |
| GO:0005737 cytoplasm | IEA GO_REF:0000002 | ACCEPT | Summary: cytoplasm: a core subcellular location for DPYSL2 (cytoplasmic/cytoskeletal CRMP). Reason: Correct core localization for a cytoskeleton-associated cytoplasmic protein. |
| GO:0005829 cytosol | IEA GO_REF:0000044 | ACCEPT | Summary: cytosol: a core subcellular location for DPYSL2 (cytoplasmic/cytoskeletal CRMP). Reason: Correct core localization for a cytoskeleton-associated cytoplasmic protein. |
| GO:0005856 cytoskeleton | IEA GO_REF:0000044 | ACCEPT | Summary: cytoskeleton: a core subcellular location for DPYSL2 (cytoplasmic/cytoskeletal CRMP). Reason: Correct core localization for a cytoskeleton-associated cytoplasmic protein. |
| GO:0016020 membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: membrane: a secondary/broad or context-specific localization for DPYSL2. Reason: Plausible but non-core (broad term, division-/synapse-specific, or high-throughput proteomics). |
| 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/DPYSL2/DPYSL2-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/DPYSL2/DPYSL2-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:0005515 protein binding | IPI PMID:21900206 A directed protein interaction network for investigating int... | REMOVE | Summary: The cited interaction evidence is retained as context, but the generic protein-binding term does not specify a molecular function. Reason: PMID:21900206 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:24722188 Protein interaction network of alternatively spliced isoform... | REMOVE | Summary: The cited interaction evidence is retained as context, but the generic protein-binding term does not specify a molecular function. Reason: PMID:24722188 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: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 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: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:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: The cited interaction evidence is retained as context, but the generic protein-binding term does not specify a molecular function. Reason: PMID:32814053 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 PMID:36950384 Protein interaction studies in human induced neurons indicat... | REMOVE | Summary: The cited interaction evidence is retained as context, but the generic protein-binding term does not specify a molecular function. Reason: PMID:36950384 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:40205054 Multimodal cell maps as a foundation for structural and func... | REMOVE | Summary: The cited interaction evidence is retained as context, but the generic protein-binding term does not specify a molecular function. Reason: PMID:40205054 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:0042802 identical protein binding | IPI PMID:21516116 Next-generation sequencing to generate interactome datasets. | 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:0042802 identical protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | 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:0042802 identical protein binding | IPI PMID:29892012 An interactome perturbation framework prioritizes damaging m... | 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:0042802 identical protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | 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:0042802 identical protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | 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:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: cytosol: a core subcellular location for DPYSL2 (cytoplasmic/cytoskeletal CRMP). Reason: Correct core localization for a cytoskeleton-associated cytoplasmic protein. |
| GO:0015630 microtubule cytoskeleton | IDA GO_REF:0000052 | ACCEPT | Summary: microtubule cytoskeleton: a core subcellular location for DPYSL2 (cytoplasmic/cytoskeletal CRMP). Reason: Correct core localization for a cytoskeleton-associated cytoplasmic protein. |
| GO:0045171 intercellular bridge | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: intercellular bridge: a secondary/broad or context-specific localization for DPYSL2. Reason: Plausible but non-core (broad term, division-/synapse-specific, or high-throughput proteomics). |
| GO:0072686 mitotic spindle | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: mitotic spindle: a secondary/broad or context-specific localization for DPYSL2. Reason: Plausible but non-core (broad term, division-/synapse-specific, or high-throughput proteomics). |
| GO:0005829 cytosol | IDA PMID:20801876 Collapsin response mediator protein-2 (Crmp2) regulates traf... | ACCEPT | Summary: cytosol: a core subcellular location for DPYSL2 (cytoplasmic/cytoskeletal CRMP). Reason: Correct core localization for a cytoskeleton-associated cytoplasmic protein. |
| GO:0005874 microtubule | IDA PMID:20801876 Collapsin response mediator protein-2 (Crmp2) regulates traf... | ACCEPT | Summary: microtubule: a core subcellular location for DPYSL2 (cytoplasmic/cytoskeletal CRMP). Reason: Correct core localization for a cytoskeleton-associated cytoplasmic protein. |
| GO:0006897 endocytosis | IMP PMID:20801876 Collapsin response mediator protein-2 (Crmp2) regulates traf... | ACCEPT | Summary: DPYSL2 links endocytic regulatory proteins to dynein-dependent vesicular transport. Reason: PMID:20801876 identifies a MICAL-L1 interaction and trafficking changes resolved by microtubule or dynein perturbation. This is a mechanistic trafficking function of the protein in non-neuronal cells, not merely a downstream developmental phenotype. Supporting Evidence: PMID:20801876 Crmp2 is an important endocytic regulatory protein that links MICAL-L1·EHD1-based vesicular transport to dynein motors. |
| GO:0016020 membrane | IDA PMID:20801876 Collapsin response mediator protein-2 (Crmp2) regulates traf... | KEEP AS NON CORE | Summary: membrane: a secondary/broad or context-specific localization for DPYSL2. Reason: Plausible but non-core (broad term, division-/synapse-specific, or high-throughput proteomics). |
| GO:0070062 extracellular exosome | HDA PMID:20458337 MHC class II-associated proteins in B-cell exosomes and pote... | KEEP AS NON CORE | Summary: extracellular exosome: a secondary/broad or context-specific localization for DPYSL2. Reason: Plausible but non-core (broad term, division-/synapse-specific, or high-throughput proteomics). |
| GO:0005829 cytosol | TAS Reactome:R-HSA-399951 | ACCEPT | Summary: cytosol: a core subcellular location for DPYSL2 (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 DPYSL2 (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 DPYSL2 (cytoplasmic/cytoskeletal CRMP). Reason: Correct core localization for a cytoskeleton-associated cytoplasmic protein. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-443783 | ACCEPT | Summary: cytosol: a core subcellular location for DPYSL2 (cytoplasmic/cytoskeletal CRMP). Reason: Correct core localization for a cytoskeleton-associated cytoplasmic protein. |
| GO:0005515 protein binding | IPI PMID:19235893 Protein product of CLN6 gene responsible for variant late-on... | REMOVE | Summary: The cited interaction evidence is retained as context, but the generic protein-binding term does not specify a molecular function. Reason: PMID:19235893 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:0007010 cytoskeleton organization | ISS GO_REF:0000024 | ACCEPT | Summary: cytoskeleton organization: a core neuronal/cytoskeletal process for the CRMP family (DPYSL2 acts in semaphorin-driven cytoskeleton remodeling and neurite/axon development). Reason: Core biological process for a CRMP-family cytoskeletal regulator. |
| GO:0005515 protein binding | IPI PMID:16260607 CRMP-2 is involved in kinesin-1-dependent transport of the S... | MODIFY | Summary: CRMP2 links the Sra-1/WAVE1 cargo complex to kinesin-1. Reason: The primary study demonstrates binding to the kinesin light chain and linkage of kinesin to the Sra-1/WAVE1 complex, establishing an adaptor function rather than an unspecified physical interaction. Proposed replacements: molecular adaptor activity Supporting Evidence: PMID:16260607 CRMP-2 interacted with the light chain of kinesin-1 and linked kinesin-1 to the Sra-1/WAVE1 complex. |
| GO:0004157 dihydropyrimidinase activity | TAS PMID:8973361 A novel gene family defined by human dihydropyrimidinase and... | REMOVE | Summary: Legacy positive dihydropyrimidinase activity (TAS, PMID:8973361) from an early report, superseded by the finding that DPYSL2 lacks the catalytic metal-binding residues. Reason: Retain rejection of the positive legacy catalytic assertion because independent structural work demonstrates loss of the CRMP2 enzymatic active site. The accessible 1996 abstract supplies homology, not positive activity evidence; the rejection rests on later target structural evidence, not an inference that the unavailable full text assayed the wrong gene. Supporting Evidence: file:human/DPYSL2/DPYSL2-uniprot.txt Lacks most of the conserved residues that are essential for PMID:28044206 they have lost the enzymatic active site. |
| GO:0006139 nucleobase-containing compound metabolic process | TAS PMID:8973361 A novel gene family defined by human dihydropyrimidinase and... | UNDECIDED | Summary: The legacy broad metabolic-process assertion cannot be judged solely from loss of dihydropyrimidinase catalysis. Reason: PMID:8973361 is available here only as an abstract documenting cloning, homology and expression. GO:0006139 covers metabolism of nucleobases, nucleotides and nucleic acids; loss of one hydrolytic reaction does not exclude noncatalytic participation in that broad process. A relevant metabolic role is not established by the accessible material, but absence of the original full text prevents a confident source-level rejection. Keep the specific catalytic rejection separate. The existing CRMP1 OpenScientist report addresses this shared legacy issue, but its abstract-only verification does not settle the full-text question; no duplicate adjudication is needed. Supporting Evidence: PMID:8973361 We have isolated cDNA clones encoding dihydropyrimidinase (DHPase) from human liver and its three homologues from human fetal brain. file:human/CRMP1/CRMP1-hypotheses/function-hypothesis-go-0016812/openscientist.md **PMID:8973361 abstract verification**: confirmed paper contains cloning and naming only, no enzymatic assay. |
| GO:0007165 signal transduction | TAS PMID:8973361 A novel gene family defined by human dihydropyrimidinase and... | ACCEPT | Summary: DPYSL2 transduces semaphorin signals into changes in neuronal cytoskeletal organization. Reason: Signal transduction is broad but accurately covers a central CRMP2 function. The direct cytoskeletal effector role is not peripheral merely because more specific downstream developmental terms exist. Supporting Evidence: PMID:23373749 participate in signaling transduction, cytoskeleton rearrangements, and endocytosis. |
| GO:0007399 nervous system development | TAS PMID:8973361 A novel gene family defined by human dihydropyrimidinase and... | ACCEPT | Summary: nervous system development: a core neuronal/cytoskeletal process for the CRMP family (DPYSL2 acts in semaphorin-driven cytoskeleton remodeling and neurite/axon development). Reason: Core biological process for a CRMP-family cytoskeletal regulator. |
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Download this section (compressed HTML)Q: How does CRMP2 (DPYSL2) select tubulin heterodimers to promote microtubule assembly, and how do sequential GSK3B/CDK5/ROCK phosphorylations switch this binding off during semaphorin-3A-induced growth-cone collapse?
Experiment: Reconstitute microtubule assembly with purified CRMP2 phospho-mimetic/phospho-dead variants and measure tubulin-heterodimer binding and axon outgrowth in neurons.
Hypothesis: Map the CRMP2 phospho-states that toggle tubulin binding.
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