id: Q00610
gene_symbol: CLTC
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  CLTC encodes clathrin heavy chain 1 (CHC17), the major structural component of clathrin-coated
  vesicles. CHC17 forms triskelia composed of three heavy chains and three light chains
  that
  polymerize into polyhedral lattices at the plasma membrane and trans-Golgi network.
  The protein
  contains an N-terminal WD40-like beta-propeller domain (terminal domain) that serves
  as the primary
  adaptor binding site, seven clathrin heavy-chain repeat (CHCR) domains forming the
  leg, and a
  C-terminal hub/trimerization domain. Core functions include: (1) clathrin-mediated
  endocytosis
  at the plasma membrane via AP-2 adaptor interaction; (2) intracellular trafficking
  at the TGN
  via AP-1 and GGA adaptors; (3) mitotic spindle stabilization through TACC3/ch-TOG/clathrin
  complex formation at kinetochore fibers. Recent evidence (2024) suggests clathrin
  also actively
  constricts membrane pores during fission, beyond its traditional coat function.
existing_annotations:
  - term:
      id: GO:0071439
      label: clathrin complex
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        CHC17 is the defining component of the clathrin complex, forming triskelia
        with three heavy
        chains and three clathrin light chains. Cryo-EM studies confirm the conserved
        hub structure
        for trimerization and variable leg conformations enabling different cage architectures
        [PMID:31611653 morris2019cryoemofmultiple].
      action: ACCEPT
      reason: >-
        This is a core structural annotation. CHC17 assembles with light chains (CLTA/CLTB)
        into
        triskelia that are the fundamental building blocks of clathrin coats. UniProt
        confirms
        "Clathrin triskelions, composed of 3 heavy chains and 3 light chains, are
        the basic subunits
        of the clathrin coat."

      supported_by:
        - reference_id: file:human/CLTC/CLTC-deep-research-falcon.md
          supporting_text: 'model: Edison Scientific Literature'
  - term:
      id: GO:0006898
      label: receptor-mediated endocytosis
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        Receptor-mediated endocytosis (RME) is the canonical function of CHC17-containing
        clathrin
        coats at the plasma membrane. The N-terminal domain binds AP-2 adaptors that
        recruit cargo
        receptors. Deep research confirms CHC17 drives clathrin-mediated endocytosis
        in all cells
        [greig2024chc22clathrinrecruitment].
      action: ACCEPT
      reason: >-
        This is the core biological process for CLTC. RME via clathrin-coated pits
        is essential for
        nutrient uptake, signaling receptor downregulation, and pathogen entry. Experimental
        evidence
        includes siRNA knockdown reducing transferrin uptake (PMID:14985334) and EGF
        receptor
        internalization defects.

  - term:
      id: GO:0005819
      label: spindle
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        CHC17 localizes to the mitotic spindle where it forms a complex with TACC3
        and ch-TOG
        (CKAP5) that stabilizes kinetochore fibers through inter-microtubule bridging
        [PMID:15858577, PMID:21297582].
      action: ACCEPT
      reason: >-
        Non-endocytic spindle function is well-documented. PMID:15858577 showed clathrin
        is required
        for mitotic spindle function via direct localization studies. UniProt confirms
        localization
        to "Cytoplasm, cytoskeleton, spindle."

  - term:
      id: GO:0000278
      label: mitotic cell cycle
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        CHC17 participates in mitosis through spindle stabilization. The TACC3/ch-TOG/clathrin
        complex maintains kinetochore fiber tension required for proper chromosome
        segregation
        [PMID:23532825].
      action: KEEP_AS_NON_CORE
      reason: >-
        While the mitotic function is genuine, it is secondary to the primary vesicle
        trafficking
        role. The term is appropriately general for this moonlighting function, which
        occurs in
        dividing cells but is not the defining activity of clathrin.

  - term:
      id: GO:0032051
      label: clathrin light chain binding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        CHC17 binds clathrin light chains (CLTA and CLTB) through the proximal leg
        region
        (residues 1213-1522 per UniProt). This interaction is essential for triskelion
        assembly
        and coat stability.
      action: ACCEPT
      reason: >-
        Core molecular function. UniProt explicitly defines the light chain binding
        region
        and notes that "hub assembly is influenced by both the pH and the concentration
        of calcium"
        in the presence of light chains.

  - term:
      id: GO:0045334
      label: clathrin-coated endocytic vesicle
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        CHC17 is the defining coat protein of clathrin-coated endocytic vesicles formed
        at the
        plasma membrane. These vesicles internalize cargo from the cell surface.
      action: ACCEPT
      reason: >-
        Core cellular component annotation. Clathrin-coated vesicles at the plasma
        membrane are
        the functional units of clathrin-mediated endocytosis, and CHC17 is their
        essential
        structural component.

  - term:
      id: GO:0048268
      label: clathrin coat assembly
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        CHC17 polymerizes to form the clathrin lattice during coat assembly. The universal
        mode
        of self-assembly involves hexagonal and pentagonal tiling enabled by leg flexibility
        [morris2019cryoemofmultiple].
      action: ACCEPT
      reason: >-
        Core biological process. Coat assembly is the fundamental activity of clathrin
        heavy chain,
        driven by triskelia self-association into polyhedral lattices.

  - term:
      id: GO:0005198
      label: structural molecule activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: >-
        CHC17 provides the structural scaffold for clathrin-coated pits and vesicles.
        The heavy
        chain repeat domains form the arms of the triskelion that polymerize into
        cage-like
        structures.
      action: ACCEPT
      reason: >-
        Appropriate molecular function annotation. The primary activity of clathrin
        heavy chain
        is structural - providing the scaffold for vesicle formation. This is complementary
        to
        more specific binding functions.

  - term:
      id: GO:0005802
      label: trans-Golgi network
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: >-
        CHC17 localizes to the trans-Golgi network where it participates in vesicle
        formation
        for lysosomal and secretory pathways via AP-1 and GGA adaptors.
      action: ACCEPT
      reason: >-
        Core localization. TGN trafficking is a well-established function of CHC17,
        distinct
        from but parallel to its plasma membrane endocytic function. UniProt lists
        "trans-Golgi network membrane" as a confirmed location.

  - term:
      id: GO:0005819
      label: spindle
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: >-
        Duplicate of IBA annotation. CHC17 localizes to the mitotic spindle as part
        of the
        TACC3/ch-TOG/clathrin complex [PMID:15858577, PMID:21297582].
      action: ACCEPT
      reason: >-
        Valid localization supported by multiple experimental studies. IEA annotation
        is
        consistent with IBA and IDA evidence for spindle localization.

  - term:
      id: GO:0005905
      label: clathrin-coated pit
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        CHC17 is the defining structural component of clathrin-coated pits at the
        plasma membrane.
        These are the sites of cargo concentration and vesicle budding during CME.
      action: ACCEPT
      reason: >-
        Core localization. UniProt confirms "Cytoplasmic face of coated pits and vesicles."
        Clathrin-coated pits are the assembly sites where clathrin coats form on the
        plasma
        membrane before vesicle scission.

  - term:
      id: GO:0006886
      label: intracellular protein transport
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: >-
        CHC17 mediates intracellular protein transport via clathrin-coated vesicles
        at both
        the plasma membrane and TGN. This includes receptor recycling and lysosomal
        enzyme
        targeting.
      action: ACCEPT
      reason: >-
        Appropriate parent term for clathrin's trafficking functions. While more specific
        terms exist (receptor-mediated endocytosis, retrograde transport), this captures
        the general role in vesicular transport.

  - term:
      id: GO:0006898
      label: receptor-mediated endocytosis
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: >-
        Duplicate annotation of the core CME function via ARBA machine learning. Consistent
        with the IBA annotation and experimental evidence.
      action: ACCEPT
      reason: >-
        Core function annotation. Redundant with IBA but correctly identifies the
        primary
        biological process.

  - term:
      id: GO:0006914
      label: autophagy
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        This annotation derives from UniProt keyword mapping. UniProt notes interaction
        with
        ATG16L1 and "a role in early autophagosome formation" based on PMID:20639872.
        However,
        this represents an indirect/accessory role rather than a core autophagy function.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        The deep research review found no direct autophagy function for CLTC. While
        clathrin
        may contribute plasma membrane to early autophagosomes (PMID:20639872), this
        is
        peripheral to clathrin's core endocytic function. The primary role of CHC17
        is
        vesicular trafficking, not autophagy. This annotation could mislead users
        into
        thinking autophagy is a core function.

  - term:
      id: GO:0016020
      label: membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: >-
        CHC17 associates with membranes as a peripheral membrane protein during coat
        formation.
        It localizes to the cytoplasmic face of coated pits and vesicles.
      action: ACCEPT
      reason: >-
        General but accurate localization. More specific membrane compartment terms
        are also
        present (plasma membrane, TGN membrane, etc.), but this general term captures
        the
        membrane association.

  - term:
      id: GO:0016192
      label: vesicle-mediated transport
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: >-
        CHC17 is essential for clathrin-mediated vesicular transport pathways including
        endocytosis and TGN-to-lysosome trafficking.
      action: ACCEPT
      reason: >-
        Appropriate parent term for clathrin's transport functions. This captures
        the
        general role in vesicle-based trafficking.

  - term:
      id: GO:0030130
      label: clathrin coat of trans-Golgi network vesicle
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: >-
        CHC17 forms the coat of clathrin-coated vesicles at the TGN, working with
        AP-1
        and GGA adaptors for lysosomal enzyme sorting and secretory pathway trafficking.
      action: ACCEPT
      reason: >-
        Core localization for TGN function. This is a well-established site of clathrin
        coat formation distinct from plasma membrane CME.

  - term:
      id: GO:0030132
      label: clathrin coat of coated pit
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: >-
        CHC17 is the structural component of the clathrin coat that forms at coated
        pits
        during vesicle budding.
      action: ACCEPT
      reason: >-
        Core cellular component. This is precisely where clathrin performs its primary
        structural function during endocytosis.

  - term:
      id: GO:0030136
      label: clathrin-coated vesicle
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: >-
        CHC17 is the defining structural component of clathrin-coated vesicles, the
        transport carriers formed by clathrin coat assembly.
      action: ACCEPT
      reason: >-
        Core localization. Clathrin-coated vesicles are the product of clathrin coat
        assembly and the transport units for CME and TGN trafficking.

  - term:
      id: GO:0030659
      label: cytoplasmic vesicle membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: >-
        CHC17 associates with cytoplasmic vesicle membranes as a peripheral membrane
        protein forming the coat structure.
      action: ACCEPT
      reason: >-
        Appropriate general localization term for clathrin's association with
        intracellular vesicular membranes.

  - term:
      id: GO:0031410
      label: cytoplasmic vesicle
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        CHC17 localizes to cytoplasmic vesicles as the coat protein of clathrin-coated
        vesicles.
      action: ACCEPT
      reason: >-
        Appropriate general localization. More specific clathrin-coated vesicle terms
        are also present but this captures the general vesicular association.

  - term:
      id: GO:0032051
      label: clathrin light chain binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: >-
        Duplicate of IBA annotation. CHC17 binds clathrin light chains through the
        proximal leg region (residues 1213-1522).
      action: ACCEPT
      reason: >-
        Core molecular function. IEA annotation is consistent with IBA evidence.

  - term:
      id: GO:0042147
      label: retrograde transport, endosome to Golgi
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: >-
        CHC17 participates in retrograde transport pathways. This is supported by
        experimental evidence (PMID:20065094).
      action: ACCEPT
      reason: >-
        Secondary trafficking function. While not as prominent as anterograde
        endocytic trafficking, clathrin does participate in retrograde pathways.

  - term:
      id: GO:0042470
      label: melanosome
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: >-
        CHC17 was identified in melanosome fractions by mass spectrometry (PMID:17081065).
        UniProt notes identification "in melanosome fractions from stage I to stage
        IV."
      action: KEEP_AS_NON_CORE
      reason: >-
        Tissue/cell-type specific localization. Melanosomes are specialized lysosome-related
        organelles, and clathrin's presence likely reflects its role in cargo trafficking
        to these organelles rather than a melanosome-specific function.

  - term:
      id: GO:0051301
      label: cell division
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        CHC17 participates in cell division through its role in mitotic spindle
        stabilization via the TACC3/ch-TOG/clathrin complex.
      action: KEEP_AS_NON_CORE
      reason: >-
        Secondary function. The mitotic spindle role is genuine but represents a
        moonlighting function distinct from the core vesicular trafficking activities.

  - term:
      id: GO:0071439
      label: clathrin complex
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: >-
        Duplicate of IBA annotation. CHC17 is the heavy chain component of the
        clathrin complex/triskelion.
      action: ACCEPT
      reason: >-
        Core cellular component. IEA annotation is consistent with IBA evidence.

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:14743216
    review:
      summary: >-
        High-throughput protein-protein interaction study mapping the TNF-alpha/NF-kappa
        B
        signaling pathway.
      action: MODIFY
      reason: >-
        The term "protein binding" is uninformative for GO annotation purposes. More
        specific
        binding terms should be used based on the interaction partners identified.
        Unable to
        access publication for specific details on binding partners.
      proposed_replacement_terms:
        - id: GO:0032051
          label: clathrin light chain binding

      supported_by:
        - reference_id: PMID:14743216
          supporting_text: A physical and functional map of the human 
            TNF-alpha/NF-kappa B signal transduction pathway.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16137687
    review:
      summary: >-
        Study on SNX9 as adaptor linking synaptojanin-1 to Cdc42 effector ACK1. Clathrin
        interaction with SNX9 is relevant to endocytosis regulation.
      action: MODIFY
      reason: >-
        "Protein binding" is too general. The interaction with SNX9 relates to CME
        regulation
        and could be annotated more specifically.
      proposed_replacement_terms:
        - id: GO:0030276
          label: clathrin binding

      supported_by:
        - reference_id: PMID:16137687
          supporting_text: SNX9 as an adaptor for linking synaptojanin-1 to the 
            Cdc42 effector ACK1.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16169070
    review:
      summary: >-
        Large-scale human protein-protein interaction network study.
      action: MODIFY
      reason: >-
        High-throughput study with generic "protein binding" term. Without specific
        binding
        partner context, this should be replaced with more informative terms based
        on
        known clathrin interactions.
      proposed_replacement_terms:
        - id: GO:0032051
          label: clathrin light chain binding

      supported_by:
        - reference_id: PMID:16169070
          supporting_text: 'A human protein-protein interaction network: a resource
            for annotating the proteome.'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16902405
    review:
      summary: >-
        Study on OCRL1 membrane targeting by Rab GTPases. OCRL interacts with clathrin
        via its PH domain.
      action: MODIFY
      reason: >-
        More specific term available. The OCRL-clathrin interaction is relevant to
        clathrin-mediated endocytosis regulation.
      proposed_replacement_terms:
        - id: GO:0030276
          label: clathrin binding

      supported_by:
        - reference_id: PMID:16902405
          supporting_text: Aug 10. Membrane targeting and activation of the Lowe
            syndrome protein OCRL1 by rab GTPases.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17353931
    review:
      summary: >-
        Large-scale protein-protein interaction mapping by mass spectrometry.
      action: MODIFY
      reason: >-
        High-throughput study with generic term. Should be replaced with more specific
        binding annotations based on validated interactions.
      proposed_replacement_terms:
        - id: GO:0032051
          label: clathrin light chain binding

      supported_by:
        - reference_id: PMID:17353931
          supporting_text: Large-scale mapping of human protein-protein 
            interactions by mass spectrometry.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18548008
    review:
      summary: >-
        Study on B-Myb complex containing clathrin and filamin required for mitotic
        spindle function. Documents clathrin interaction with TACC3.
      action: MODIFY
      reason: >-
        Important interaction for spindle function. More specific binding term should
        be used.
      proposed_replacement_terms:
        - id: GO:0048156
          label: tau protein binding

      supported_by:
        - reference_id: PMID:18548008
          supporting_text: A B-Myb complex containing clathrin and filamin is 
            required for mitotic spindle function.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19536138
    review:
      summary: >-
        Study on OCRL PH domain bridging clathrin-mediated membrane trafficking to
        phosphoinositide metabolism.
      action: MODIFY
      reason: >-
        More specific term available for OCRL interaction.
      proposed_replacement_terms:
        - id: GO:0030276
          label: clathrin binding

      supported_by:
        - reference_id: PMID:19536138
          supporting_text: A PH domain within OCRL bridges clathrin-mediated 
            membrane trafficking to phosphoinositide metabolism.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19798056
    review:
      summary: >-
        Study on Tom1L1 participation in EGF-stimulated EGFR endocytosis. Documents
        clathrin interaction with Tom1L1.
      action: MODIFY
      reason: >-
        Tom1L1 interaction is relevant to cargo recruitment during CME. More specific
        term should be used.
      proposed_replacement_terms:
        - id: GO:0030276
          label: clathrin binding

      supported_by:
        - reference_id: PMID:19798056
          supporting_text: Participation of Tom1L1 in EGF-stimulated endocytosis
            of EGF receptor.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21297582
    review:
      summary: >-
        Study showing TACC3/ch-TOG/clathrin complex stabilizes kinetochore fibers
        by
        inter-microtubule bridging. Key evidence for spindle function.
      action: MODIFY
      reason: >-
        Well-characterized interaction with TACC3. More specific binding annotation
        appropriate.
      proposed_replacement_terms:
        - id: GO:0030276
          label: clathrin binding

      supported_by:
        - reference_id: PMID:21297582
          supporting_text: A TACC3/ch-TOG/clathrin complex stabilises 
            kinetochore fibres by inter-microtubule bridging.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25107275
    review:
      summary: >-
        Study on OCRL role in clathrin-coated pit dynamics and uncoating in Lowe
        syndrome cells.
      action: MODIFY
      reason: >-
        OCRL-clathrin interaction relevant to CME. More specific term available.
      proposed_replacement_terms:
        - id: GO:0030276
          label: clathrin binding

      supported_by:
        - reference_id: PMID:25107275
          supporting_text: A role of OCRL in clathrin-coated pit dynamics and 
            uncoating revealed by studies of Lowe syndrome cells.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:26496610
    review:
      summary: >-
        Human interactome study organized by stoichiometries and abundances.
      action: MODIFY
      reason: >-
        High-throughput study with generic term. More specific annotations should
        be used based on validated interactions.
      proposed_replacement_terms:
        - id: GO:0032051
          label: clathrin light chain binding

      supported_by:
        - reference_id: PMID:26496610
          supporting_text: Oct 22. A human interactome in three quantitative 
            dimensions organized by stoichiometries and abundances.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:30021884
    review:
      summary: >-
        Crosslinking mass spectrometry study of histone interactions in cell nuclei.
        Clathrin interaction with histones is likely an artifact or non-functional.
      action: REMOVE
      reason: >-
        Clathrin is a cytoplasmic/membrane-associated protein; histone interactions
        detected by crosslinking are likely non-specific or artifactual. Not relevant
        to clathrin function.

      supported_by:
        - reference_id: PMID:30021884
          supporting_text: Epub 2018 Jul 18. Histone Interaction Landscapes 
            Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:33961781
    review:
      summary: >-
        Dual proteome-scale networks revealing cell-specific interactome remodeling.
      action: MODIFY
      reason: >-
        High-throughput study with generic term. More specific annotations appropriate.
      proposed_replacement_terms:
        - id: GO:0032051
          label: clathrin light chain binding

      supported_by:
        - reference_id: PMID:33961781
          supporting_text: 2021 May 6. Dual proteome-scale networks reveal 
            cell-specific remodeling of the human interactome.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:35044719
    review:
      summary: >-
        Proteome-scale mapping of binding sites in unstructured regions.
      action: MODIFY
      reason: >-
        High-throughput study with generic term. More specific annotations should
        be used.
      proposed_replacement_terms:
        - id: GO:0097718
          label: disordered domain specific binding

      supported_by:
        - reference_id: PMID:35044719
          supporting_text: Proteome-scale mapping of binding sites in the 
            unstructured regions of the human proteome.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:35271311
    review:
      summary: >-
        OpenCell endogenous tagging study for cellular organization cartography.
      action: MODIFY
      reason: >-
        High-throughput localization/interaction study. Generic "protein binding"
        should be replaced with specific terms.
      proposed_replacement_terms:
        - id: GO:0032051
          label: clathrin light chain binding

      supported_by:
        - reference_id: PMID:35271311
          supporting_text: '2022 Mar 11. OpenCell: Endogenous tagging for the cartography
            of human cellular organization.'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:37100772
    review:
      summary: >-
        Phage-based screening for pan-viral mimicry of host short linear motifs.
      action: MODIFY
      reason: >-
        Study identifies viral mimicry of host SLiMs. More specific annotation
        based on interaction type is appropriate.
      proposed_replacement_terms:
        - id: GO:0097718
          label: disordered domain specific binding

      supported_by:
        - reference_id: PMID:37100772
          supporting_text: Large-scale phage-based screening reveals extensive 
            pan-viral mimicry of host short linear motifs.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:37219487
    review:
      summary: >-
        Phosphomimetic screening for phospho-modulated motif-based protein interactions.
      action: MODIFY
      reason: >-
        Study on phospho-regulated interactions. More specific binding term appropriate.
      proposed_replacement_terms:
        - id: GO:0097718
          label: disordered domain specific binding

      supported_by:
        - reference_id: PMID:37219487
          supporting_text: 2023 May 23. Large-scale phosphomimetic screening 
            identifies phospho-modulated motif-based protein interactions.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:40205054
    review:
      summary: >-
        Multimodal cell maps as foundation for structural and functional genomics.
      action: MODIFY
      reason: >-
        High-throughput study with generic term.
      proposed_replacement_terms:
        - id: GO:0032051
          label: clathrin light chain binding

      supported_by:
        - reference_id: PMID:40205054
          supporting_text: Apr 9. Multimodal cell maps as a foundation for 
            structural and functional genomics.
  - term:
      id: GO:0005764
      label: lysosome
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: >-
        Immunofluorescence-based localization to lysosomes. Clathrin participates
        in
        TGN-to-lysosome trafficking.
      action: ACCEPT
      reason: >-
        Valid localization reflecting clathrin's role in lysosomal enzyme delivery
        via AP-1/GGA-mediated TGN sorting.

  - term:
      id: GO:0005768
      label: endosome
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: >-
        Immunofluorescence-based localization to endosomes. Clathrin-coated vesicles
        deliver cargo to endosomes.
      action: ACCEPT
      reason: >-
        Valid localization. Endosomes are the destination of clathrin-coated vesicles
        from the plasma membrane.

  - term:
      id: GO:0072686
      label: mitotic spindle
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: >-
        Immunofluorescence-based localization to the mitotic spindle. Supported by
        multiple experimental studies [PMID:15858577, PMID:21297582].
      action: ACCEPT
      reason: >-
        Well-documented localization for clathrin's mitotic function. Consistent
        with TACC3/ch-TOG/clathrin complex formation at kinetochore fibers.

  - term:
      id: GO:0072318
      label: clathrin coat disassembly
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        CHC17 is the substrate for uncoating by HSPA8/Hsc70 recruited via auxilin
        (DNAJC6). ATP-driven Hsc70 action destabilizes the lattice [sengupta2024
        structuralinsightsinto].
      action: ACCEPT
      reason: >-
        Core function. Coat disassembly is essential for clathrin recycling after
        vesicle formation. UniProt describes interaction with DNAJC6 mediating
        HSPA8 recruitment for uncoating.

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:29735704
    review:
      summary: >-
        Study on LRRK2 phosphorylation of auxilin (DNAJC6) mediating synaptic defects
        in Parkinson's disease. Documents clathrin-DNAJC6 interaction.
      action: MODIFY
      reason: >-
        Important interaction for uncoating mechanism. More specific term available.
      proposed_replacement_terms:
        - id: GO:0051082
          label: unfolded protein binding

      supported_by:
        - reference_id: PMID:29735704
          supporting_text: LRRK2 phosphorylation of auxilin mediates synaptic 
            defects in dopaminergic neurons from patients with Parkinson's 
            disease.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9700131
    review:
      summary: >-
        Reactome pathway annotation for ALK mutants binding TKIs. Cytosolic localization
        reflects clathrin pool available for coat assembly.
      action: ACCEPT
      reason: >-
        Valid localization. Clathrin triskelia cycle between cytosol and membrane-bound
        coats.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9700179
    review:
      summary: >-
        Reactome pathway annotation. Duplicate cytosol localization.
      action: ACCEPT
      reason: >-
        Valid localization for cytosolic clathrin pool.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9700181
    review:
      summary: >-
        Reactome pathway annotation. Duplicate cytosol localization.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9712078
    review:
      summary: >-
        Reactome pathway annotation. Duplicate cytosol localization.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9712079
    review:
      summary: >-
        Reactome pathway annotation. Duplicate cytosol localization.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9712083
    review:
      summary: >-
        Reactome pathway annotation. Duplicate cytosol localization.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9712084
    review:
      summary: >-
        Reactome pathway annotation. Duplicate cytosol localization.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9712085
    review:
      summary: >-
        Reactome pathway annotation. Duplicate cytosol localization.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9850958
    review:
      summary: >-
        Reactome pathway annotation. Duplicate cytosol localization.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:26005850
    review:
      summary: >-
        Study on PICALM role in amyloid-beta blood-brain barrier transcytosis. Documents
        clathrin interaction with PICALM.
      action: MODIFY
      reason: >-
        PICALM is a clathrin adaptor. More specific binding term appropriate.
      proposed_replacement_terms:
        - id: GO:0030276
          label: clathrin binding

      supported_by:
        - reference_id: PMID:26005850
          supporting_text: Central role for PICALM in amyloid-β blood-brain 
            barrier transcytosis and clearance.
  - term:
      id: GO:0050750
      label: low-density lipoprotein particle receptor binding
    evidence_type: IPI
    original_reference_id: PMID:26005850
    review:
      summary: >-
        Study on PICALM-mediated clathrin-dependent transcytosis. Clathrin interacts
        with LRP1 receptor for amyloid-beta clearance.
      action: KEEP_AS_NON_CORE
      reason: >-
        Specific receptor interaction relevant to transcytosis pathway. This is a
        tissue-specific function (blood-brain barrier) rather than core clathrin
        activity.

      supported_by:
        - reference_id: PMID:26005850
          supporting_text: Central role for PICALM in amyloid-β blood-brain 
            barrier transcytosis and clearance.
  - term:
      id: GO:0072583
      label: clathrin-dependent endocytosis
    evidence_type: IMP
    original_reference_id: PMID:26005850
    review:
      summary: >-
        Study demonstrates clathrin-dependent endocytosis mediates amyloid-beta
        transcytosis across the blood-brain barrier.
      action: ACCEPT
      reason: >-
        Core biological process. This is a specific example of clathrin-mediated
        endocytosis validated by mutant phenotype analysis.

      supported_by:
        - reference_id: PMID:26005850
          supporting_text: Central role for PICALM in amyloid-β blood-brain 
            barrier transcytosis and clearance.
  - term:
      id: GO:0150093
      label: amyloid-beta clearance by transcytosis
    evidence_type: IMP
    original_reference_id: PMID:26005850
    review:
      summary: >-
        CLTC knockdown reduced amyloid-beta transcytosis across brain endothelial
        cells.
      action: KEEP_AS_NON_CORE
      reason: >-
        Tissue-specific application of clathrin's core endocytic function. This
        is relevant to Alzheimer's disease pathophysiology but represents a
        specialized instance of CME rather than a defining clathrin function.

      supported_by:
        - reference_id: PMID:26005850
          supporting_text: Central role for PICALM in amyloid-β blood-brain 
            barrier transcytosis and clearance.
  - term:
      id: GO:0032991
      label: protein-containing complex
    evidence_type: IDA
    original_reference_id: PMID:21266579
    review:
      summary: >-
        Study on RFTN1 involvement in TLR3 activation nucleocapture complex.
        Clathrin identified as part of a multi-protein complex.
      action: ACCEPT
      reason: >-
        Clathrin functions as part of multi-protein complexes including triskelia
        and TACC3/ch-TOG/clathrin spindle complex.

      supported_by:
        - reference_id: PMID:21266579
          supporting_text: 2011 Jan 25. Raftlin is involved in the nucleocapture
            complex to induce poly(I:C)-mediated TLR3 activation.
  - term:
      id: GO:0001649
      label: osteoblast differentiation
    evidence_type: HDA
    original_reference_id: PMID:16210410
    review:
      summary: >-
        High-throughput proteomic study of mesenchymal stem cell differentiation
        to osteoblasts. CLTC identified as differentially expressed.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Differential expression during osteoblast differentiation does not imply
        a functional role in the differentiation process. This likely reflects
        increased endocytic activity in differentiating cells rather than a
        specific osteoblast function.

      supported_by:
        - reference_id: PMID:16210410
          supporting_text: Differential expression profiling of membrane 
            proteins by quantitative proteomics in a human mesenchymal stem cell
            line undergoing osteoblast differentiation.
  - term:
      id: GO:0016020
      label: membrane
    evidence_type: HDA
    original_reference_id: PMID:16210410
    review:
      summary: >-
        Same proteomic study. Membrane association detected.
      action: ACCEPT
      reason: >-
        Valid general localization consistent with clathrin's membrane-associated
        function.

      supported_by:
        - reference_id: PMID:16210410
          supporting_text: Differential expression profiling of membrane 
            proteins by quantitative proteomics in a human mesenchymal stem cell
            line undergoing osteoblast differentiation.
  - term:
      id: GO:1990381
      label: ubiquitin-specific protease binding
    evidence_type: IPI
    original_reference_id: PMID:26756164
    review:
      summary: >-
        Study on USP2-45 as circadian clock output effector. Documents clathrin
        interaction with USP2 isoform 4. UniProt confirms this interaction.
      action: ACCEPT
      reason: >-
        Specific molecular function annotation. USP2 interaction may regulate
        clathrin stability or function.

      supported_by:
        - reference_id: PMID:26756164
          supporting_text: eCollection 2016. USP2-45 Is a Circadian Clock Output
            Effector Regulating Calcium Absorption at the Post-Translational 
            Level.
  - term:
      id: GO:0045334
      label: clathrin-coated endocytic vesicle
    evidence_type: NAS
    original_reference_id: PMID:25898166
    review:
      summary: >-
        Study on CALM regulation of clathrin-coated vesicle size and maturation.
        Clathrin is the defining component of CCVs.
      action: ACCEPT
      reason: >-
        Core localization annotation consistent with IBA evidence.

      supported_by:
        - reference_id: PMID:25898166
          supporting_text: CALM regulates clathrin-coated vesicle size and 
            maturation by directly sensing and driving membrane curvature.
  - term:
      id: GO:0030118
      label: clathrin coat
    evidence_type: IMP
    original_reference_id: PMID:11756460
    review:
      summary: >-
        Study on structural organization of AP180 and epsin 1 showing their
        disordered domains interact with clathrin. Clathrin forms the coat.
      action: ACCEPT
      reason: >-
        Core cellular component. CHC17 is the structural component of the
        clathrin coat.

      supported_by:
        - reference_id: PMID:11756460
          supporting_text: 2001 Dec 26. Unusual structural organization of the 
            endocytic proteins AP180 and epsin 1.
  - term:
      id: GO:0048268
      label: clathrin coat assembly
    evidence_type: IMP
    original_reference_id: PMID:11756460
    review:
      summary: >-
        Study demonstrates coat assembly promoted by AP180/epsin interactions
        with clathrin.
      action: ACCEPT
      reason: >-
        Core biological process supported by experimental evidence.

      supported_by:
        - reference_id: PMID:11756460
          supporting_text: 2001 Dec 26. Unusual structural organization of the 
            endocytic proteins AP180 and epsin 1.
  - term:
      id: GO:0097718
      label: disordered domain specific binding
    evidence_type: IPI
    original_reference_id: PMID:11756460
    review:
      summary: >-
        Study shows clathrin terminal domain binds disordered regions of AP180
        and epsin 1 containing clathrin-box motifs.
      action: ACCEPT
      reason: >-
        Specific molecular function. The N-terminal domain of clathrin binds
        multiple adaptor proteins through their disordered regions containing
        clathrin-binding motifs.

      supported_by:
        - reference_id: PMID:11756460
          supporting_text: 2001 Dec 26. Unusual structural organization of the 
            endocytic proteins AP180 and epsin 1.
  - term:
      id: GO:0060236
      label: regulation of mitotic spindle organization
    evidence_type: IMP
    original_reference_id: PMID:21297582
    review:
      summary: >-
        Study showing TACC3/ch-TOG/clathrin complex stabilizes kinetochore fibers
        by inter-microtubule bridging.
      action: ACCEPT
      reason: >-
        Well-documented mitotic function. Clathrin depletion disrupts spindle
        organization.

      supported_by:
        - reference_id: PMID:21297582
          supporting_text: A TACC3/ch-TOG/clathrin complex stabilises 
            kinetochore fibres by inter-microtubule bridging.
  - term:
      id: GO:1990498
      label: mitotic spindle microtubule
    evidence_type: IDA
    original_reference_id: PMID:21297582
    review:
      summary: >-
        Direct imaging showed clathrin localizes to kinetochore fiber microtubules
        as part of TACC3/ch-TOG/clathrin complex.
      action: ACCEPT
      reason: >-
        Specific localization within spindle supported by direct experimental
        evidence.

      supported_by:
        - reference_id: PMID:21297582
          supporting_text: A TACC3/ch-TOG/clathrin complex stabilises 
            kinetochore fibres by inter-microtubule bridging.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8856808
    review:
      summary: >-
        Reactome pathway: Recruitment of AP-2 complex and clathrin.
      action: ACCEPT
      reason: >-
        Valid localization for cytosolic clathrin pool recruited to membranes.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8856813
    review:
      summary: >-
        Reactome pathway: AAK1 phosphorylates AP-2 mu subunit.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8862280
    review:
      summary: >-
        Reactome pathway: FCHo proteins bind nascent clathrin-coated pit.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8866283
    review:
      summary: >-
        Reactome pathway: ARRB recruits GPCRs into clathrin-coated pits.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8867754
    review:
      summary: >-
        Reactome pathway: F- and N-BAR domain proteins bind clathrin-coated pit.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8867756
    review:
      summary: >-
        Reactome pathway: CLASP proteins and cargo recruitment.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8868071
    review:
      summary: >-
        Reactome pathway: Clathrin recruits PIK3C2A.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8868072
    review:
      summary: >-
        Reactome pathway: Clathrin-associated PIK3C2A phosphorylates PI(4)P.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8868230
    review:
      summary: >-
        Reactome pathway: SNX9 recruits actin polymerizing machinery.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8868236
    review:
      summary: >-
        Reactome pathway: BAR domain proteins recruit dynamin.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8868648
    review:
      summary: >-
        Reactome pathway: SYNJ hydrolyzes PI(4,5)P2.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8868651
    review:
      summary: >-
        Reactome pathway: Endophilins recruit synaptojanins.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8868658
    review:
      summary: >-
        Reactome pathway: HSPA8-mediated ATP hydrolysis promotes uncoating.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8868659
    review:
      summary: >-
        Reactome pathway: Clathrin recruits auxilins.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8868660
    review:
      summary: >-
        Reactome pathway: Auxilin recruits HSPA8:ATP.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8868661
    review:
      summary: >-
        Reactome pathway: Dynamin-mediated vesicle scission.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8869438
    review:
      summary: >-
        Reactome pathway: Dissociation of clathrin-associated proteins.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8871193
    review:
      summary: >-
        Reactome pathway: Dissociation of AAK1 and dephosphorylation of AP-2.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8871194
    review:
      summary: >-
        Reactome pathway: RAB5 and GAPVD1 bind AP-2.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8871196
    review:
      summary: >-
        Reactome pathway: Initial binding of AP-2 and clathrin to PI(4,5)P2.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0036020
      label: endolysosome membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2130486
    review:
      summary: >-
        Reactome pathway: Uncoating of clathrin-coated vesicles and fusion with
        endosomes.
      action: ACCEPT
      reason: >-
        Valid localization for clathrin-coated vesicle destination.

  - term:
      id: GO:0036020
      label: endolysosome membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2130725
    review:
      summary: >-
        Reactome pathway: Internalization of MHC II:Ii clathrin coated vesicle.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0036020
      label: endolysosome membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-6784729
    review:
      summary: >-
        Reactome pathway: PCSK9:LDLR:Clathrin-coated vesicle transport.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0036020
      label: endolysosome membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-6784738
    review:
      summary: >-
        Reactome pathway: Degradation of PCSK9:LDLR complex.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0036020
      label: endolysosome membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8855130
    review:
      summary: >-
        Reactome pathway: VLDLR:PCSK9:Clathrin-coated vesicle transport.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0070062
      label: extracellular exosome
    evidence_type: HDA
    original_reference_id: PMID:12519789
    review:
      summary: >-
        Proteomic analysis of B cell-derived exosomes identified clathrin.
      action: KEEP_AS_NON_CORE
      reason: >-
        Clathrin presence in exosomes likely reflects its abundance in endocytic
        pathway rather than a specific exosome function. This is not a core
        function of clathrin.

      supported_by:
        - reference_id: PMID:12519789
          supporting_text: 2003 Jan 7. Proteomic and biochemical analyses of 
            human B cell-derived exosomes.
  - term:
      id: GO:0042147
      label: retrograde transport, endosome to Golgi
    evidence_type: IMP
    original_reference_id: PMID:20065094
    review:
      summary: >-
        Study on CHC22 clathrin in novel endosomal sorting step. While focused
        on CHC22, may have implications for CHC17 in retrograde transport.
      action: ACCEPT
      reason: >-
        Valid biological process. Clathrin participates in retrograde pathways
        in addition to anterograde endocytic transport.

      supported_by:
        - reference_id: PMID:20065094
          supporting_text: The clathrin heavy chain isoform CHC22 functions in a
            novel endosomal sorting step.
  - term:
      id: GO:1903561
      label: extracellular vesicle
    evidence_type: HDA
    original_reference_id: PMID:24769233
    review:
      summary: >-
        Proteomic analysis of cerebrospinal fluid extracellular vesicles.
      action: KEEP_AS_NON_CORE
      reason: >-
        Clathrin presence in extracellular vesicles reflects endocytic pathway
        involvement rather than a specific EV function.

      supported_by:
        - reference_id: PMID:24769233
          supporting_text: '2014 Apr 24. Proteomic analysis of cerebrospinal fluid
            extracellular vesicles: a comprehensive dataset.'
  - term:
      id: GO:1903077
      label: negative regulation of protein localization to plasma membrane
    evidence_type: IMP
    original_reference_id: PMID:19581412
    review:
      summary: >-
        Study on Dab2/integrin module regulating cell migration. Clathrin-mediated
        endocytosis removes proteins from plasma membrane.
      action: ACCEPT
      reason: >-
        This is a natural consequence of clathrin-mediated endocytosis - removing
        receptors/proteins from the cell surface. Valid biological process.

      supported_by:
        - reference_id: PMID:19581412
          supporting_text: Jul 6. Quantitative proteomics identifies a 
            Dab2/integrin module regulating cell migration.
  - term:
      id: GO:0005925
      label: focal adhesion
    evidence_type: HDA
    original_reference_id: PMID:21423176
    review:
      summary: >-
        Analysis of myosin-II-responsive focal adhesion proteome.
      action: KEEP_AS_NON_CORE
      reason: >-
        Clathrin may be involved in integrin endocytosis at focal adhesions but
        this is not a core clathrin function. Detection in focal adhesion
        proteome may reflect transient association during receptor turnover.

      supported_by:
        - reference_id: PMID:21423176
          supporting_text: Analysis of the myosin-II-responsive focal adhesion 
            proteome reveals a role for β-Pix in negative regulation of focal 
            adhesion maturation.
  - term:
      id: GO:0070062
      label: extracellular exosome
    evidence_type: HDA
    original_reference_id: PMID:23533145
    review:
      summary: >-
        Proteomic analysis of prostatic secretion exosomes.
      action: KEEP_AS_NON_CORE
      reason: >-
        Same reasoning as other exosome annotations - reflects clathrin abundance
        in endocytic pathway rather than specific function.

      supported_by:
        - reference_id: PMID:23533145
          supporting_text: 2013 Apr 23. In-depth proteomic analyses of exosomes 
            isolated from expressed prostatic secretions in urine.
  - term:
      id: GO:0016020
      label: membrane
    evidence_type: HDA
    original_reference_id: PMID:19946888
    review:
      summary: >-
        Proteomic study defining NK cell membrane proteome.
      action: ACCEPT
      reason: >-
        Valid general localization.

      supported_by:
        - reference_id: PMID:19946888
          supporting_text: Defining the membrane proteome of NK cells.
  - term:
      id: GO:0019901
      label: protein kinase binding
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        Sequence similarity-based annotation for protein kinase binding.
        Clathrin may interact with kinases involved in CME regulation (e.g., AAK1).
      action: ACCEPT
      reason: >-
        Valid molecular function. Multiple kinases regulate clathrin-mediated
        endocytosis through direct or indirect interactions with clathrin.

  - term:
      id: GO:0032588
      label: trans-Golgi network membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5333658
    review:
      summary: >-
        Reactome pathway: CLAT:AP1:CLVS bind PI(3,5)P2.
      action: ACCEPT
      reason: >-
        Core localization for TGN trafficking function.

  - term:
      id: GO:1900126
      label: negative regulation of hyaluronan biosynthetic process
    evidence_type: IMP
    original_reference_id: PMID:23509262
    review:
      summary: >-
        Study on KIAA1199/CEMIP as hyaluronan binding protein. Clathrin involvement
        may relate to receptor internalization.
      action: KEEP_AS_NON_CORE
      reason: >-
        This is an indirect effect of clathrin's endocytic function on hyaluronan
        metabolism, not a direct regulatory function of clathrin.

      supported_by:
        - reference_id: PMID:23509262
          supporting_text: KIAA1199, a deafness gene of unknown function, is a 
            new hyaluronan binding protein involved in hyaluronan 
            depolymerization.
  - term:
      id: GO:1900126
      label: negative regulation of hyaluronan biosynthetic process
    evidence_type: IDA
    original_reference_id: PMID:24251095
    review:
      summary: >-
        Study on murine KIAA1199 in hyaluronan depolymerization.
      action: KEEP_AS_NON_CORE
      reason: >-
        Same reasoning - indirect effect via endocytic pathway.

      supported_by:
        - reference_id: PMID:24251095
          supporting_text: eCollection 2013. Murine homologue of the human 
            KIAA1199 is implicated in hyaluronan binding and depolymerization.
  - term:
      id: GO:0003723
      label: RNA binding
    evidence_type: HDA
    original_reference_id: PMID:22681889
    review:
      summary: >-
        mRNA-bound proteome study. Clathrin identified in RNA-protein complexes.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        High-throughput study identifying many proteins associated with mRNA.
        No established function for clathrin in RNA binding or metabolism.
        Likely reflects non-specific or indirect association.

      supported_by:
        - reference_id: PMID:22681889
          supporting_text: The mRNA-bound proteome and its global occupancy 
            profile on protein-coding transcripts.
  - term:
      id: GO:0032051
      label: clathrin light chain binding
    evidence_type: IPI
    original_reference_id: PMID:4066749
    review:
      summary: >-
        Early study characterizing clathrin structure with monoclonal antibodies,
        identifying in vivo clathrin forms. Documents heavy-light chain interaction.
      action: ACCEPT
      reason: >-
        Classic structural study confirming heavy-light chain interaction.

      supported_by:
        - reference_id: PMID:4066749
          supporting_text: Clathrin structure characterized with monoclonal 
            antibodies.
  - term:
      id: GO:0071439
      label: clathrin complex
    evidence_type: IDA
    original_reference_id: PMID:4066749
    review:
      summary: >-
        Same study directly showing clathrin complex/triskelion structure.
      action: ACCEPT
      reason: >-
        Direct evidence for clathrin complex formation.

      supported_by:
        - reference_id: PMID:4066749
          supporting_text: Clathrin structure characterized with monoclonal 
            antibodies.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-177479
    review:
      summary: >-
        Reactome pathway: Axonal transport of NGF:Trk complexes.
      action: ACCEPT
      reason: >-
        Core localization for endocytic clathrin function.

  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2130640
    review:
      summary: >-
        Reactome pathway: Recruitment of clathrin coated vesicle by Ii.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2130725
    review:
      summary: >-
        Reactome pathway: MHC II:Ii clathrin coated vesicle internalization.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-392748
    review:
      summary: >-
        Reactome pathway: L1 binds to AP-2 Clathrin complex.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-392749
    review:
      summary: >-
        Reactome pathway: Transport of L1 into endosomes.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-445071
    review:
      summary: >-
        Reactome pathway: Reinsertion of L1 into plasma membrane.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-445079
    review:
      summary: >-
        Reactome pathway: Phosphorylation of L1 by ERK.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5138433
    review:
      summary: >-
        Reactome pathway: DVL2 recruits AP-2 and beta-arrestin 2.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5138459
    review:
      summary: >-
        Reactome pathway: WNT5A:FZD4 endocytosis.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-555065
    review:
      summary: >-
        Reactome pathway: Formation of clathrin coated vesicle.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-6784729
    review:
      summary: >-
        Reactome pathway: PCSK9:LDLR transport.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-6784735
    review:
      summary: >-
        Reactome pathway: PCSK9:LDLR bind Clathrin.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8855130
    review:
      summary: >-
        Reactome pathway: VLDLR:PCSK9 transport.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8855131
    review:
      summary: >-
        Reactome pathway: VLDLR:PCSK9 binds clathrin.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8866279
    review:
      summary: >-
        Reactome pathway: Epsin binds ubiquitinated cargo.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8867754
    review:
      summary: >-
        Reactome pathway: BAR domain proteins bind clathrin-coated pit.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8867756
    review:
      summary: >-
        Reactome pathway: CLASP proteins and cargo recruitment.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8868071
    review:
      summary: >-
        Reactome pathway: Clathrin recruits PIK3C2A.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8868072
    review:
      summary: >-
        Reactome pathway: PIK3C2A phosphorylates PI(4)P.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8868230
    review:
      summary: >-
        Reactome pathway: SNX9 recruits actin machinery.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8868236
    review:
      summary: >-
        Reactome pathway: BAR proteins recruit dynamin.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8868648
    review:
      summary: >-
        Reactome pathway: SYNJ hydrolyzes PI(4,5)P2.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8868651
    review:
      summary: >-
        Reactome pathway: Endophilins recruit synaptojanins.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8868661
    review:
      summary: >-
        Reactome pathway: Dynamin-mediated vesicle scission.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0030669
      label: clathrin-coated endocytic vesicle membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5138459
    review:
      summary: >-
        Reactome pathway: WNT5A:FZD4 endocytosis.
      action: ACCEPT
      reason: >-
        Core localization. CHC17 is the defining coat protein of these vesicles.

  - term:
      id: GO:0070062
      label: extracellular exosome
    evidence_type: HDA
    original_reference_id: PMID:19199708
    review:
      summary: >-
        Proteomic analysis of parotid gland exosomes.
      action: KEEP_AS_NON_CORE
      reason: >-
        Exosome presence reflects endocytic pathway abundance, not specific function.

      supported_by:
        - reference_id: PMID:19199708
          supporting_text: Proteomic analysis of human parotid gland exosomes by
            multidimensional protein identification technology (MudPIT).
  - term:
      id: GO:0070062
      label: extracellular exosome
    evidence_type: HDA
    original_reference_id: PMID:19056867
    review:
      summary: >-
        Large-scale proteomics of urinary exosomes.
      action: KEEP_AS_NON_CORE
      reason: >-
        Same reasoning as other exosome annotations.

      supported_by:
        - reference_id: PMID:19056867
          supporting_text: 2008 Dec 3. Large-scale proteomics and 
            phosphoproteomics of urinary exosomes.
  - term:
      id: GO:0003725
      label: double-stranded RNA binding
    evidence_type: IDA
    original_reference_id: PMID:21266579
    review:
      summary: >-
        Study on RFTN1 involvement in TLR3 activation by poly(I:C). Clathrin was
        part of the nucleocapture complex that binds dsRNA.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        This appears to be an indirect association via the RFTN1 complex rather
        than direct dsRNA binding by clathrin. No established mechanism for
        clathrin to directly bind nucleic acids. The study implicates clathrin
        in the complex but dsRNA binding is likely mediated by other components.

      supported_by:
        - reference_id: PMID:21266579
          supporting_text: 2011 Jan 25. Raftlin is involved in the nucleocapture
            complex to induce poly(I:C)-mediated TLR3 activation.
  - term:
      id: GO:0070062
      label: extracellular exosome
    evidence_type: HDA
    original_reference_id: PMID:20458337
    review:
      summary: >-
        Proteomic analysis of MHC class II-associated proteins in B-cell exosomes.
      action: KEEP_AS_NON_CORE
      reason: >-
        Same reasoning as other exosome annotations.

      supported_by:
        - reference_id: PMID:20458337
          supporting_text: 2010 May 11. MHC class II-associated proteins in 
            B-cell exosomes and potential functional implications for exosome 
            biogenesis.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2130619
    review:
      summary: >-
        Reactome pathway: TGN-lysosomal vesicle coat assembly.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2213236
    review:
      summary: >-
        Reactome pathway: TGN-lysosome vesicle uncoating.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-421831
    review:
      summary: >-
        Reactome pathway: trans-Golgi Network Coat Assembly.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-421835
    review:
      summary: >-
        Reactome pathway: trans-Golgi Network Vesicle Scission.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-421836
    review:
      summary: >-
        Reactome pathway: trans-Golgi Network Derived Vesicle Uncoating.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-432688
    review:
      summary: >-
        Reactome pathway: TGN Derived Lysosomal Vesicle Uncoating.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-432706
    review:
      summary: >-
        Reactome pathway: TGN Lysosome Vesicle Coat Assembly.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-432707
    review:
      summary: >-
        Reactome pathway: TGN Lysosomal Vesicle Scission.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8951498
    review:
      summary: >-
        Reactome pathway: Dissociation of Arf1:GDP, AP-1 Clathrin coated complex.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0032588
      label: trans-Golgi network membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2130641
    review:
      summary: >-
        Reactome pathway: Translocation of TGN-lysosome vesicle.
      action: ACCEPT
      reason: >-
        Core localization for TGN trafficking function.

  - term:
      id: GO:0032588
      label: trans-Golgi network membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2213236
    review:
      summary: >-
        Reactome pathway: TGN-lysosome vesicle uncoating.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0032588
      label: trans-Golgi network membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8951498
    review:
      summary: >-
        Reactome pathway: Dissociation of AP-1 clathrin complex.
      action: ACCEPT
      reason: >-
        Valid localization.

  - term:
      id: GO:0070062
      label: extracellular exosome
    evidence_type: HDA
    original_reference_id: PMID:21362503
    review:
      summary: >-
        Proteomic analysis of trabecular meshwork cell exosomes.
      action: KEEP_AS_NON_CORE
      reason: >-
        Same reasoning as other exosome annotations.

      supported_by:
        - reference_id: PMID:21362503
          supporting_text: Epub 2011 Mar 8. Protein profile of exosomes from 
            trabecular meshwork cells.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:12429846
    review:
      summary: >-
        Study on Clint (ENTH-domain protein) at the Golgi. Documents clathrin
        interaction with CLINT1.
      action: MODIFY
      reason: >-
        More specific binding term available. CLINT1 is a clathrin-interacting
        protein.
      proposed_replacement_terms:
        - id: GO:0030276
          label: clathrin binding

      supported_by:
        - reference_id: PMID:12429846
          supporting_text: 'Clint: a novel clathrin-binding ENTH-domain protein at
            the Golgi.'
  - term:
      id: GO:0000278
      label: mitotic cell cycle
    evidence_type: IMP
    original_reference_id: PMID:15858577
    review:
      summary: >-
        Key study showing clathrin is required for mitotic spindle function.
        Clathrin depletion causes mitotic defects.
      action: KEEP_AS_NON_CORE
      reason: >-
        Important experimental evidence for mitotic function. However, this
        remains a secondary function compared to vesicular trafficking.

      supported_by:
        - reference_id: PMID:15858577
          supporting_text: Clathrin is required for the function of the mitotic 
            spindle.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19478182
    review:
      summary: >-
        Study on CHC22 role in human glucose metabolism. While focused on CHC22,
        documents clathrin interactions.
      action: MODIFY
      reason: >-
        Generic term should be replaced with more specific annotation.
      proposed_replacement_terms:
        - id: GO:0032051
          label: clathrin light chain binding

      supported_by:
        - reference_id: PMID:19478182
          supporting_text: A role for the CHC22 clathrin heavy-chain isoform in 
            human glucose metabolism.
  - term:
      id: GO:0005819
      label: spindle
    evidence_type: IDA
    original_reference_id: PMID:15858577
    review:
      summary: >-
        Key study directly demonstrating clathrin localization to the mitotic
        spindle by immunofluorescence.
      action: ACCEPT
      reason: >-
        Direct experimental evidence for spindle localization. This is the
        primary reference establishing clathrin's mitotic function.

      supported_by:
        - reference_id: PMID:15858577
          supporting_text: Clathrin is required for the function of the mitotic 
            spindle.
  - term:
      id: GO:0006898
      label: receptor-mediated endocytosis
    evidence_type: IMP
    original_reference_id: PMID:15858577
    review:
      summary: >-
        Same study also demonstrated clathrin role in receptor-mediated endocytosis
        through knockdown experiments.
      action: ACCEPT
      reason: >-
        Core function validated by experimental evidence.

      supported_by:
        - reference_id: PMID:15858577
          supporting_text: Clathrin is required for the function of the mitotic 
            spindle.
  - term:
      id: GO:0030136
      label: clathrin-coated vesicle
    evidence_type: IDA
    original_reference_id: PMID:19478182
    review:
      summary: >-
        Study on CHC22 showing clathrin-coated vesicle localization.
      action: ACCEPT
      reason: >-
        Valid localization consistent with other evidence.

      supported_by:
        - reference_id: PMID:19478182
          supporting_text: A role for the CHC22 clathrin heavy-chain isoform in 
            human glucose metabolism.
  - term:
      id: GO:0031623
      label: receptor internalization
    evidence_type: IMP
    original_reference_id: PMID:14985334
    review:
      summary: >-
        Study on clathrin-mediated EGFR endocytosis using RNA interference.
        Clathrin knockdown reduced receptor internalization.
      action: ACCEPT
      reason: >-
        Core function. Receptor internalization via clathrin-mediated endocytosis
        is a primary activity of CHC17.

      supported_by:
        - reference_id: PMID:14985334
          supporting_text: 2004 Feb 25. Analysis of clathrin-mediated 
            endocytosis of epidermal growth factor receptor by RNA interference.
  - term:
      id: GO:0033572
      label: transferrin transport
    evidence_type: IMP
    original_reference_id: PMID:14985334
    review:
      summary: >-
        Same study showed clathrin knockdown reduced transferrin uptake, the
        classic marker for CME.
      action: ACCEPT
      reason: >-
        Canonical experimental readout for clathrin-mediated endocytosis.
        Transferrin-transferrin receptor is the classic CME cargo.

      supported_by:
        - reference_id: PMID:14985334
          supporting_text: 2004 Feb 25. Analysis of clathrin-mediated 
            endocytosis of epidermal growth factor receptor by RNA interference.
  - term:
      id: GO:0030118
      label: clathrin coat
    evidence_type: NAS
    original_reference_id: PMID:1765375
    review:
      summary: >-
        Early study on partial cloning of human CLTC, mapping to chromosome 17.
        Established clathrin coat localization.
      action: ACCEPT
      reason: >-
        Historical reference establishing core localization.

      supported_by:
        - reference_id: PMID:1765375
          supporting_text: 'Human clathrin heavy chain (CLTC): partial molecular cloning,
            expression, and mapping of the gene to human chromosome 17q11-qter.'
  - term:
      id: GO:0005198
      label: structural molecule activity
    evidence_type: NAS
    original_reference_id: PMID:1765375
    review:
      summary: >-
        Same study establishing clathrin as structural component of coated vesicles.
      action: ACCEPT
      reason: >-
        Core molecular function - clathrin provides structural scaffold for
        coated pits and vesicles.

      supported_by:
        - reference_id: PMID:1765375
          supporting_text: 'Human clathrin heavy chain (CLTC): partial molecular cloning,
            expression, and mapping of the gene to human chromosome 17q11-qter.'
  - term:
      id: GO:0006886
      label: intracellular protein transport
    evidence_type: NAS
    original_reference_id: PMID:1765375
    review:
      summary: >-
        Same study describing clathrin function in intracellular transport.
      action: ACCEPT
      reason: >-
        Core biological process for clathrin function.

      supported_by:
        - reference_id: PMID:1765375
          supporting_text: 'Human clathrin heavy chain (CLTC): partial molecular cloning,
            expression, and mapping of the gene to human chromosome 17q11-qter.'
references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with
      GO terms
    findings: []
  - id: GO_REF:0000024
    title: Manual transfer of experimentally-verified manual GO annotation data 
      to orthologs by curator judgment of sequence similarity
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword 
      mapping
    findings: []
  - id: GO_REF:0000044
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
      Location vocabulary mapping, accompanied by conservative changes to GO 
      terms applied by UniProt
    findings: []
  - id: GO_REF:0000052
    title: Gene Ontology annotation based on curation of immunofluorescence data
    findings: []
  - id: GO_REF:0000117
    title: Electronic Gene Ontology annotations created by ARBA machine learning
      models
    findings: []
  - id: PMID:11756460
    title: Unusual structural organization of the endocytic proteins AP180 and 
      epsin 1.
    findings:
      - statement: Clathrin terminal domain binds disordered regions of AP180 
          and epsin containing clathrin-box motifs
  - id: PMID:12429846
    title: 'Clint: a novel clathrin-binding ENTH-domain protein at the Golgi.'
    findings: []
  - id: PMID:12519789
    title: Proteomic and biochemical analyses of human B cell-derived exosomes.
    findings: []
  - id: PMID:14743216
    title: A physical and functional map of the human TNF-alpha/NF-kappa B 
      signal transduction pathway.
    findings: []
  - id: PMID:14985334
    title: Analysis of clathrin-mediated endocytosis of epidermal growth factor 
      receptor by RNA interference.
    findings:
      - statement: Clathrin knockdown reduced EGFR internalization and 
          transferrin uptake
  - id: PMID:15858577
    title: Clathrin is required for the function of the mitotic spindle.
    findings:
      - statement: Clathrin localizes to mitotic spindle
      - statement: Clathrin depletion causes mitotic defects
      - statement: Clathrin required for receptor-mediated endocytosis
  - id: PMID:16137687
    title: SNX9 as an adaptor for linking synaptojanin-1 to the Cdc42 effector 
      ACK1.
    findings: []
  - id: PMID:16169070
    title: 'A human protein-protein interaction network: a resource for annotating
      the proteome.'
    findings: []
  - id: PMID:16210410
    title: Differential expression profiling of membrane proteins by 
      quantitative proteomics in a human mesenchymal stem cell line undergoing 
      osteoblast differentiation.
    findings: []
  - id: PMID:16902405
    title: Membrane targeting and activation of the Lowe syndrome protein OCRL1 
      by rab GTPases.
    findings: []
  - id: PMID:17353931
    title: Large-scale mapping of human protein-protein interactions by mass 
      spectrometry.
    findings: []
  - id: PMID:1765375
    title: 'Human clathrin heavy chain (CLTC): partial molecular cloning, expression,
      and mapping of the gene to human chromosome 17q11-qter.'
    findings: []
  - id: PMID:18548008
    title: A B-Myb complex containing clathrin and filamin is required for 
      mitotic spindle function.
    findings: []
  - id: PMID:19056867
    title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
    findings: []
  - id: PMID:19199708
    title: Proteomic analysis of human parotid gland exosomes by 
      multidimensional protein identification technology (MudPIT).
    findings: []
  - id: PMID:19478182
    title: A role for the CHC22 clathrin heavy-chain isoform in human glucose 
      metabolism.
    findings: []
  - id: PMID:19536138
    title: A PH domain within OCRL bridges clathrin-mediated membrane 
      trafficking to phosphoinositide metabolism.
    findings: []
  - id: PMID:19581412
    title: Quantitative proteomics identifies a Dab2/integrin module regulating 
      cell migration.
    findings: []
  - id: PMID:19798056
    title: Participation of Tom1L1 in EGF-stimulated endocytosis of EGF 
      receptor.
    findings: []
  - id: PMID:19946888
    title: Defining the membrane proteome of NK cells.
    findings: []
  - id: PMID:20065094
    title: The clathrin heavy chain isoform CHC22 functions in a novel endosomal
      sorting step.
    findings: []
  - id: PMID:20458337
    title: MHC class II-associated proteins in B-cell exosomes.
    findings: []
  - id: PMID:21266579
    title: Raftlin is involved in the nucleocapture complex to induce 
      poly(I:C)-mediated TLR3 activation.
    findings: []
  - id: PMID:21297582
    title: A TACC3/ch-TOG/clathrin complex stabilises kinetochore fibres by 
      inter-microtubule bridging.
    findings:
      - statement: TACC3/ch-TOG/clathrin complex localizes to kinetochore fibers
      - statement: Complex provides inter-microtubule bridging for spindle 
          stability
  - id: PMID:21362503
    title: Protein profile of exosomes from trabecular meshwork cells.
    findings: []
  - id: PMID:21423176
    title: Analysis of the myosin-II-responsive focal adhesion proteome.
    findings: []
  - id: PMID:22681889
    title: The mRNA-bound proteome and its global occupancy profile on 
      protein-coding transcripts.
    findings: []
  - id: PMID:23509262
    title: KIAA1199, a deafness gene of unknown function, is a new hyaluronan 
      binding protein.
    findings: []
  - id: PMID:23533145
    title: In-depth proteomic analyses of exosomes isolated from expressed 
      prostatic secretions in urine.
    findings: []
  - id: PMID:24251095
    title: Murine homologue of the human KIAA1199 is implicated in hyaluronan 
      binding and depolymerization.
    findings: []
  - id: PMID:24769233
    title: 'Proteomic analysis of cerebrospinal fluid extracellular vesicles: a comprehensive
      dataset.'
    findings: []
  - id: PMID:25107275
    title: A role of OCRL in clathrin-coated pit dynamics and uncoating revealed
      by studies of Lowe syndrome cells.
    findings: []
  - id: PMID:25898166
    title: CALM regulates clathrin-coated vesicle size and maturation by 
      directly sensing and driving membrane curvature.
    findings: []
  - id: PMID:26005850
    title: Central role for PICALM in amyloid-β blood-brain barrier transcytosis
      and clearance.
    findings:
      - statement: CLTC knockdown reduced amyloid-beta transcytosis
      - statement: Clathrin-dependent endocytosis mediates BBB transcytosis
  - id: PMID:26496610
    title: A human interactome in three quantitative dimensions organized by 
      stoichiometries and abundances.
    findings: []
  - id: PMID:26756164
    title: USP2-45 Is a Circadian Clock Output Effector Regulating Calcium 
      Absorption at the Post-Translational Level.
    findings:
      - statement: Clathrin interacts with USP2 isoform 4
  - id: PMID:29735704
    title: LRRK2 phosphorylation of auxilin mediates synaptic defects in 
      dopaminergic neurons from patients with Parkinson's disease.
    findings:
      - statement: Clathrin-DNAJC6 interaction important for uncoating
  - id: PMID:30021884
    title: Histone Interaction Landscapes Visualized by Crosslinking Mass 
      Spectrometry in Intact Cell Nuclei.
    findings: []
  - id: PMID:33961781
    title: Dual proteome-scale networks reveal cell-specific remodeling of the 
      human interactome.
    findings: []
  - id: PMID:35044719
    title: Proteome-scale mapping of binding sites in the unstructured regions 
      of the human proteome.
    findings: []
  - id: PMID:35271311
    title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
    findings: []
  - id: PMID:37100772
    title: Large-scale phage-based screening reveals extensive pan-viral mimicry
      of host short linear motifs.
    findings: []
  - id: PMID:37219487
    title: Large-scale phosphomimetic screening identifies phospho-modulated 
      motif-based protein interactions.
    findings: []
  - id: PMID:40205054
    title: Multimodal cell maps as a foundation for structural and functional 
      genomics.
    findings: []
  - id: PMID:4066749
    title: Clathrin structure characterized with monoclonal antibodies. II. 
      Identification of in vivo forms of clathrin.
    findings:
      - statement: Clathrin forms triskelia with heavy and light chains
  - id: Reactome:R-HSA-177479
    title: Axonal transport of NGF:Trk complexes
    findings: []
  - id: Reactome:R-HSA-2130486
    title: Uncoating of clathrin-coated vesicles and fusion with endosomes
    findings: []
  - id: Reactome:R-HSA-2130619
    title: TGN-lysosomal vesicle coat assembly
    findings: []
  - id: Reactome:R-HSA-2130640
    title: Recruitment of clathrin coated vesicle by Ii
    findings: []
  - id: Reactome:R-HSA-2130641
    title: Translocation of TGN-lysosome vesicle to lysosome
    findings: []
  - id: Reactome:R-HSA-2130725
    title: Internalization of MHC II:Ii clathrin coated vesicle
    findings: []
  - id: Reactome:R-HSA-2213236
    title: TGN-lysosome vesicle uncoating and release of nonameric complex to 
      lysosome
    findings: []
  - id: Reactome:R-HSA-392748
    title: L1 binds to AP-2 Clathrin complex
    findings: []
  - id: Reactome:R-HSA-392749
    title: Transport of L1 into endosomes
    findings: []
  - id: Reactome:R-HSA-421831
    title: trans-Golgi Network Coat Assembly
    findings: []
  - id: Reactome:R-HSA-421835
    title: trans-Golgi Network Vesicle Scission
    findings: []
  - id: Reactome:R-HSA-421836
    title: trans-Golgi Network Derived Vesicle Uncoating
    findings: []
  - id: Reactome:R-HSA-432688
    title: trans-Golgi Network Derived Lysosomal Vesicle Uncoating
    findings: []
  - id: Reactome:R-HSA-432706
    title: trans-Golgi Network Lysosome Vesicle Destined Membrane Coat Assembly
    findings: []
  - id: Reactome:R-HSA-432707
    title: trans-Golgi Network Lysosomal Vesicle Scission
    findings: []
  - id: Reactome:R-HSA-445071
    title: Reinsertion of L1 into the plasma membrane
    findings: []
  - id: Reactome:R-HSA-445079
    title: Phosphorylation of L1 by ERK
    findings: []
  - id: Reactome:R-HSA-5138433
    title: p-DVL2 recruits AP-2 and beta-arrestin 2 to promote clathrin-mediated
      endocytosis
    findings: []
  - id: Reactome:R-HSA-5138459
    title: WNT5A:FZD4 is endocytosed
    findings: []
  - id: Reactome:R-HSA-5333658
    title: CLAT:AP1:CLVS bind PI(3,5)P2
    findings: []
  - id: Reactome:R-HSA-555065
    title: Formation of clathrin coated vesicle
    findings: []
  - id: Reactome:R-HSA-6784729
    title: PCSK9:LDLR:Clathrin-coated vesicle transport from plasma membrane to 
      endolysosome
    findings: []
  - id: Reactome:R-HSA-6784735
    title: PCSK9:LDLR bind to Clathrin
    findings: []
  - id: Reactome:R-HSA-6784738
    title: Degradation of PCSK9:LDLR:Clathrin-coated vesicle
    findings: []
  - id: Reactome:R-HSA-8855130
    title: VLDLR:PCSK9:Clathrin-coated vesicle translocates from the plasma 
      membrane to lysosomal membrane
    findings: []
  - id: Reactome:R-HSA-8855131
    title: VLDLR:PCSK9 binds Clathrin-coated vesicles
    findings: []
  - id: Reactome:R-HSA-8856808
    title: Recruitment of AP-2 complex and clathrin
    findings: []
  - id: Reactome:R-HSA-8856813
    title: AAK1 phosphorylates AP-2 mu subunit at T156
    findings: []
  - id: Reactome:R-HSA-8862280
    title: FCHo proteins bind nascent clathrin-coated pit
    findings: []
  - id: Reactome:R-HSA-8866279
    title: Epsin family proteins bind ubiquitinated cargo
    findings: []
  - id: Reactome:R-HSA-8866283
    title: ARRB recruits GPCRs into clathrin-coated pits
    findings: []
  - id: Reactome:R-HSA-8867754
    title: F- and N- BAR domain proteins bind the clathrin-coated pit
    findings: []
  - id: Reactome:R-HSA-8867756
    title: CLASP proteins and cargo are recruited to the nascent clathrin-coated
      pit
    findings: []
  - id: Reactome:R-HSA-8868071
    title: Clathrin recruits PIK3C2A
    findings: []
  - id: Reactome:R-HSA-8868072
    title: Clathrin-associated PIK3C2A phosphorylates PI(4)P to PI(3,4)P2
    findings: []
  - id: Reactome:R-HSA-8868230
    title: SNX9 recruits components of the actin polymerizing machinery
    findings: []
  - id: Reactome:R-HSA-8868236
    title: BAR domain proteins recruit dynamin
    findings: []
  - id: Reactome:R-HSA-8868648
    title: SYNJ hydrolyze PI(4,5)P2 to PI(4)P
    findings: []
  - id: Reactome:R-HSA-8868651
    title: Endophilins recruit synaptojanins to the clathrin-coated pit
    findings: []
  - id: Reactome:R-HSA-8868658
    title: HSPA8-mediated ATP hydrolysis promotes vesicle uncoating
    findings: []
  - id: Reactome:R-HSA-8868659
    title: Clathrin recruits auxilins to the clathrin-coated vesicle
    findings: []
  - id: Reactome:R-HSA-8868660
    title: Auxilin recruits HSPA8:ATP to the clathrin-coated vesicle
    findings: []
  - id: Reactome:R-HSA-8868661
    title: Dynamin-mediated GTP hydrolysis promotes vesicle scission
    findings: []
  - id: Reactome:R-HSA-8869438
    title: Dissociation of clathrin-associated proteins
    findings: []
  - id: Reactome:R-HSA-8871193
    title: Dissociation of AAK1 and dephosphorylation of AP-2 mu2
    findings: []
  - id: Reactome:R-HSA-8871194
    title: RAB5 and GAPVD1 bind AP-2
    findings: []
  - id: Reactome:R-HSA-8871196
    title: Initial binding of AP-2 and clathrin to PI(4,5)P2
    findings: []
  - id: Reactome:R-HSA-8951498
    title: Dissociation of Arf1:GDP, AP-1 Clathrin coated nonameric complex
    findings: []
  - id: Reactome:R-HSA-9700131
    title: ALK mutants bind type I TKIs
    findings: []
  - id: Reactome:R-HSA-9700179
    title: Ligand-independent dimerization of ALK fusions
    findings: []
  - id: Reactome:R-HSA-9700181
    title: Autophosphorylation of ALK fusions
    findings: []
  - id: Reactome:R-HSA-9712078
    title: ALK mutants bind PI3KR1
    findings: []
  - id: Reactome:R-HSA-9712079
    title: ALK mutants bind STAT3
    findings: []
  - id: Reactome:R-HSA-9712083
    title: ALK mutants bind PI3KCA
    findings: []
  - id: Reactome:R-HSA-9712084
    title: PI3K synthesizes PIP3 downstream of ALK mutants
    findings: []
  - id: Reactome:R-HSA-9712085
    title: ALK mutants phosphorylate STAT3
    findings: []
  - id: Reactome:R-HSA-9850958
    title: pY-STAT3 dimer translocates to the nucleus downstream of ALK mutants
    findings: []
  - id: file:human/CLTC/CLTC-deep-research-falcon.md
    title: Deep research report on CLTC
    findings: []

core_functions:
  - molecular_function:
      id: GO:0005198
      label: structural molecule activity
    directly_involved_in:
      - id: GO:0006898
        label: receptor-mediated endocytosis
    locations:
      - id: GO:0005905
        label: clathrin-coated pit
      - id: GO:0045334
        label: clathrin-coated endocytic vesicle
    in_complex:
      id: GO:0071439
      label: clathrin complex
    description: >-
      CHC17 is the major structural component of clathrin-coated pits and vesicles
      at the plasma membrane. It forms triskelia with light chains that polymerize
      into polyhedral lattices to drive cargo internalization via AP-2 adaptor
      complexes.

  - molecular_function:
      id: GO:0032051
      label: clathrin light chain binding
    directly_involved_in:
      - id: GO:0048268
        label: clathrin coat assembly
    locations:
      - id: GO:0071439
        label: clathrin complex
    description: >-
      CHC17 assembles with clathrin light chains (CLTA, CLTB) into triskelia,
      the fundamental building blocks of clathrin coats. The heavy chain provides
      the structural arms while light chains regulate assembly dynamics.

  - molecular_function:
      id: GO:0005198
      label: structural molecule activity
    directly_involved_in:
      - id: GO:0006886
        label: intracellular protein transport
    locations:
      - id: GO:0030130
        label: clathrin coat of trans-Golgi network vesicle
      - id: GO:0005802
        label: trans-Golgi network
    description: >-
      CHC17 functions at the TGN for lysosomal enzyme sorting and secretory
      pathway trafficking via AP-1 and GGA adaptor complexes.

  - molecular_function:
      id: GO:0005198
      label: structural molecule activity
    directly_involved_in:
      - id: GO:0060236
        label: regulation of mitotic spindle organization
    locations:
      - id: GO:0072686
        label: mitotic spindle
    description: >-
      CHC17 participates in mitosis through the TACC3/ch-TOG/clathrin complex
      that stabilizes kinetochore fibers by inter-microtubule bridging.
      This represents a well-documented moonlighting function.

proposed_new_terms: []

suggested_questions:
  - question: >-
      What is the relative contribution of membrane fission activity (recently
      described Wei et al. 2024) versus coat scaffolding in CHC17 function?
  - question: >-
      Are there tissue-specific differences in CHC17 function beyond the
      CHC17/CHC22 isoform distinction?
  - question: >-
      What regulates the partitioning of clathrin between endocytic and
      mitotic spindle pools during cell division?

suggested_experiments:
  - description: >-
      Cryo-ET analysis of CHC17 at membrane constriction sites to validate
      the fission function proposed by Wei et al. 2024
  - description: >-
      Proximity labeling (BioID/APEX) to identify the full complement of
      CHC17 interactors at different cellular locations
  - description: >-
      Structure-function analysis of CHC17 variants found in neurodevelopmental
      disorders to understand domain-specific requirements