DPYSL4

# yaml-language-server: $schema=../../../src/ai_gene_review/schema/gene_review.yaml
id: O14531
gene_symbol: DPYSL4
product_type: PROTEIN
status: DRAFT
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: Dihydropyrimidinase-related protein 4 (DPYSL4/CRMP3), a cytoplasmic CRMP-family protein involved
  in class-3 semaphorin signaling and cytoskeletal remodeling during neuronal development. A catalytically
  dead member of the metallo-dependent hydrolase (dihydropyrimidinase) superfamily, it lacks the conserved
  metal-cofactor residues and has no dihydropyrimidinase activity. It binds filamin, forms homo- and hetero-tetramers
  with other CRMPs, and contributes to neurite outgrowth and dendritic development.
existing_annotations:
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: 'cytosol: a core subcellular location for DPYSL4 (cytoplasmic/cytoskeletal CRMP).'
    action: ACCEPT
    reason: Correct core localization for a cytoskeleton-associated cytoplasmic protein.
- term:
    id: GO:0006208
    label: pyrimidine nucleobase catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  negated: true
  review:
    summary: 'NOT: DPYSL4 is not involved in pyrimidine nucleobase catabolism (the process counterpart
      of the absent dihydropyrimidinase activity).'
    action: ACCEPT
    reason: Correct negation, consistent with loss of catalytic activity. Retain.
    supported_by:
    - reference_id: file:human/DPYSL4/DPYSL4-uniprot.txt
      supporting_text: Lacks most of the conserved residues that are essential for
- term:
    id: GO:0016812
    label: hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in cyclic amides
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Positive 'hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in cyclic
      amides' propagated from the metallo-hydrolase fold signature (IBA). DPYSL4 lacks the catalytic metal
      site, and the curated dihydropyrimidinase activity is itself NOT-ed.
    action: REMOVE
    reason: 'Domain/phylogenetic over-propagation refutable on biological grounds: the metal-cofactor-binding
      residues are absent (UniProt CAUTION), so no metallo-hydrolase activity is supported; the real function
      is a non-catalytic cytoskeletal regulator. Same basis as the DPYSL5 review.'
    supported_by:
    - reference_id: file:human/DPYSL4/DPYSL4-uniprot.txt
      supporting_text: Lacks most of the conserved residues that are essential for
    - reference_id: file:human/DPYSL4/DPYSL4-uniprot.txt
      supporting_text: Belongs to the metallo-dependent hydrolases superfamily.
- term:
    id: GO:0004157
    label: dihydropyrimidinase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  negated: true
  review:
    summary: 'NOT: DPYSL4 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).'
    action: ACCEPT
    reason: 'Correct, important negation: a catalytically dead family member. Retain.'
    supported_by:
    - reference_id: file:human/DPYSL4/DPYSL4-uniprot.txt
      supporting_text: Lacks most of the conserved residues that are essential for
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: 'cytoplasm: a core subcellular location for DPYSL4 (cytoplasmic/cytoskeletal CRMP).'
    action: ACCEPT
    reason: Correct core localization for a cytoskeleton-associated cytoplasmic protein.
- term:
    id: GO:0016787
    label: hydrolase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: Positive 'hydrolase activity' propagated from the metallo-hydrolase fold signature (IEA).
      DPYSL4 lacks the catalytic metal site, and the curated dihydropyrimidinase activity is itself NOT-ed.
    action: REMOVE
    reason: 'Domain/phylogenetic over-propagation refutable on biological grounds: the metal-cofactor-binding
      residues are absent (UniProt CAUTION), so no metallo-hydrolase activity is supported; the real function
      is a non-catalytic cytoskeletal regulator. Same basis as the DPYSL5 review.'
    supported_by:
    - reference_id: file:human/DPYSL4/DPYSL4-uniprot.txt
      supporting_text: Lacks most of the conserved residues that are essential for
    - reference_id: file:human/DPYSL4/DPYSL4-uniprot.txt
      supporting_text: Belongs to the metallo-dependent hydrolases superfamily.
- term:
    id: GO:0016810
    label: hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: Positive 'hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds' propagated
      from the metallo-hydrolase fold signature (IEA). DPYSL4 lacks the catalytic metal site, and the
      curated dihydropyrimidinase activity is itself NOT-ed.
    action: REMOVE
    reason: 'Domain/phylogenetic over-propagation refutable on biological grounds: the metal-cofactor-binding
      residues are absent (UniProt CAUTION), so no metallo-hydrolase activity is supported; the real function
      is a non-catalytic cytoskeletal regulator. Same basis as the DPYSL5 review.'
    supported_by:
    - reference_id: file:human/DPYSL4/DPYSL4-uniprot.txt
      supporting_text: Lacks most of the conserved residues that are essential for
    - reference_id: file:human/DPYSL4/DPYSL4-uniprot.txt
      supporting_text: Belongs to the metallo-dependent hydrolases superfamily.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21900206
  qualifier: enables
  review:
    summary: Specific protein interaction (PMID:21900206); supports DPYSL4's scaffold/adapter role but
      the generic 'protein binding' term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interaction kept as non-core supporting evidence; the informative function is captured
      in core_functions.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: Generic 'protein binding' from a high-throughput interactome screen (PMID:25416956).
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput protein binding is uninformative about molecular function (curation guideline).
      Over-annotation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: Generic 'protein binding' from a high-throughput interactome screen (PMID:32814053).
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput protein binding is uninformative about molecular function (curation guideline).
      Over-annotation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Generic 'protein binding' from a high-throughput interactome screen (PMID:33961781).
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput protein binding is uninformative about molecular function (curation guideline).
      Over-annotation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: Specific protein interaction (PMID:40205054); supports DPYSL4's scaffold/adapter role but
      the generic 'protein binding' term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interaction kept as non-core supporting evidence; the informative function is captured
      in core_functions.
- term:
    id: GO:0031005
    label: filamin binding
  evidence_type: IPI
  original_reference_id: PMID:25358863
  qualifier: enables
  review:
    summary: 'filamin binding: a specific molecular interaction consistent with DPYSL4''s cytoskeletal-adapter
      role.'
    action: ACCEPT
    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.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-399944
  qualifier: located_in
  review:
    summary: 'cytosol: a core subcellular location for DPYSL4 (cytoplasmic/cytoskeletal CRMP).'
    action: ACCEPT
    reason: Correct core localization for a cytoskeleton-associated cytoplasmic protein.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-399947
  qualifier: located_in
  review:
    summary: 'cytosol: a core subcellular location for DPYSL4 (cytoplasmic/cytoskeletal CRMP).'
    action: ACCEPT
    reason: Correct core localization for a cytoskeleton-associated cytoplasmic protein.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-399951
  qualifier: located_in
  review:
    summary: 'cytosol: a core subcellular location for DPYSL4 (cytoplasmic/cytoskeletal CRMP).'
    action: ACCEPT
    reason: Correct core localization for a cytoskeleton-associated cytoplasmic protein.
- term:
    id: GO:0007399
    label: nervous system development
  evidence_type: TAS
  original_reference_id: PMID:9652388
  qualifier: involved_in
  review:
    summary: 'nervous system development: a core neuronal/cytoskeletal process for the CRMP family (DPYSL4
      acts in semaphorin-driven cytoskeleton remodeling and neurite/axon development).'
    action: ACCEPT
    reason: Core biological process for a CRMP-family cytoskeletal regulator.
references:
- id: GO_REF:0000002
  title: GO annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified annotations to orthologs by curator judgment
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: GO annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping
  findings: []
- id: GO_REF:0000052
  title: GO annotation based on curation of immunofluorescence data (HPA)
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl
    Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: file:human/DPYSL4/DPYSL4-uniprot.txt
  title: UniProt entry for DPYSL4
  findings:
  - statement: DPYSL4 lacks the metal-cofactor-binding residues required for dihydropyrimidinase activity.
    supporting_text: Lacks most of the conserved residues that are essential for
  - statement: DPYSL4 belongs to the metallo-dependent hydrolase superfamily.
    supporting_text: Belongs to the metallo-dependent hydrolases superfamily.
- id: PMID:21900206
  title: A directed protein interaction network for investigating intracellular signal transduction.
  findings: []
- id: PMID:25358863
  title: Amino- and carboxyl-terminal domains of Filamin-A interact with CRMP1 to mediate Sema3A signalling.
  findings: []
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread
    Protein Aggregation in Affected Brains.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
- id: PMID:9652388
  title: The Ulip family phosphoproteins--common and specific properties.
  findings: []
- id: Reactome:R-HSA-399944
  title: Reactome pathway (CRMP/semaphorin signalling)
  findings: []
- id: Reactome:R-HSA-399947
  title: Reactome pathway (CRMP/semaphorin signalling)
  findings: []
- id: Reactome:R-HSA-399951
  title: Reactome pathway (CRMP/semaphorin signalling)
  findings: []
aliases:
- CRMP3
- CRMP-3
- DRP-4
- ULIP-4
- Collapsin response mediator protein 3
core_functions:
- description: Catalytically inactive CRMP-family cytoskeletal regulator acting in semaphorin-driven neuronal
    development; forms hetero-oligomers with other CRMPs.
  directly_involved_in:
  - id: GO:0007399
    label: nervous system development
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: file:human/DPYSL4/DPYSL4-uniprot.txt
    supporting_text: Lacks most of the conserved residues that are essential for
  molecular_function:
    id: GO:0031005
    label: filamin binding
suggested_questions:
- question: What is the role of CRMP3 (DPYSL4) and its filamin interaction in dendritic/neurite development,
    and how does it differ functionally from the other CRMPs within hetero-tetramers?
suggested_experiments:
- hypothesis: DPYSL4 contributes to dendritic development via filamin-dependent cytoskeletal coupling.
  description: Test dendrite/neurite outgrowth with wild-type vs filamin-binding-deficient DPYSL4 and
    in DPYSL4-depleted neurons.