RFXAP

id: O00287
gene_symbol: RFXAP
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  RFXAP (Regulatory Factor X-Associated Protein) is a scaffolding subunit of the
  heterotrimeric RFX transcription regulatory complex that controls MHC class II
  gene expression. The RFX complex consists of RFX5 (two copies), RFXAP, and
  RFXANK/RFX-B. RFXAP does NOT bind DNA directly; rather, it assembles with
  RFXANK to form a scaffold that recruits RFX5. This scaffold-RFX5 interaction
  induces a conformational change in RFX5 that exposes its DNA-binding domain,
  enabling the complex to bind the X-box motif in MHC class II promoters. RFXAP
  mutations cause MHC class II deficiency (bare lymphocyte syndrome
  complementation group D), demonstrating its essential role in MHC class II
  gene regulation. RFXAP should be classified as a transcription coactivator,
  not a DNA-binding transcription factor.
existing_annotations:
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      RFXAP localizes to the nucleus where it functions as part of the RFX
      complex. UniProt indicates nuclear localization (PMID:10938133), and
      the protein contains a nuclear localization signal at residues 163-178.
      IBA annotation is consistent with experimental evidence from multiple
      studies. Deep research confirms nuclear localization with NLS and acidic
      region essential for function (RFXAP-deep-research-falcon.md).
    action: ACCEPT
    reason: >-
      Nuclear localization is well-established for RFXAP. The protein must be
      in the nucleus to participate in the RFX complex that regulates MHC class
      II transcription. Supported by IDA evidence (PMID:10938133) and presence
      of NLS motif.
    additional_reference_ids:
      - file:human/RFXAP/RFXAP-deep-research-falcon.md
    supported_by:
      - reference_id: PMID:10938133
        supporting_text: "The bare lymphocyte syndrome, a severe combined immunodeficiency due to loss of major histocompatibility complex (MHC) class II gene expression, is caused by inherited mutations in the genes encoding the heterotrimeric transcription factor RFX (RFX-B, RFX5, and RFXAP)"
      - reference_id: file:human/RFXAP/RFXAP-deep-research-falcon.md
        supporting_text: "RFXAP is nuclear; an internal NLS and acidic (DE) region were described, and pathogenic variants within exon 1 spanning nucleotides 116-540 can affect the NLS/acidic domain and impair nuclear function"

- term:
    id: GO:0006357
    label: regulation of transcription by RNA polymerase II
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      RFXAP is an essential component of the RFX complex that regulates MHC
      class II gene transcription. The IBA annotation at this general level
      is appropriate and phylogenetically sound. Deep research confirms RFXAP
      is essential for MHC-II transcription via the RFX complex and CIITA
      recruitment (RFXAP-deep-research-falcon.md).
    action: ACCEPT
    reason: >-
      As a component of the RFX transcription regulatory complex, RFXAP is
      clearly involved in regulation of transcription by RNA polymerase II.
      This is a core function supported by extensive literature including
      PMID:9118943 and PMID:9806546. The general term is appropriate for
      IBA evidence.
    additional_reference_ids:
      - file:human/RFXAP/RFXAP-deep-research-falcon.md
    supported_by:
      - reference_id: PMID:9118943
        supporting_text: "RFXAP, a novel subunit of the RFX DNA binding complex is mutated in MHC class II deficiency"
      - reference_id: PMID:9806546
        supporting_text: "RFX5 and RFXAP are two subunits of RFX, a multi-protein complex that binds the X box motif of MHC-II promoters"
      - reference_id: file:human/RFXAP/RFXAP-deep-research-falcon.md
        supporting_text: "RFXAP is one of three core proteins (RFX5, RFXAP, RFXANK) that assemble into the RFX complex recognizing the X-box within MHC class II promoters"

- term:
    id: GO:0003677
    label: DNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      This IEA annotation is INCORRECT. RFXAP does NOT bind DNA directly.
      The DNA-binding subunit of the RFX complex is RFX5, which contains
      the DNA-binding domain. RFXAP serves as a scaffolding protein that
      helps assemble the complex and induces a conformational change in
      RFX5 to expose its DNA-binding domain.
    action: REMOVE
    reason: >-
      Multiple studies demonstrate that RFXAP does not bind DNA directly.
      The Nature Genetics paper (PMID:9806546) clearly states that RFX5 is
      the DNA-binding subunit. The EMBO paper (PMID:9118943) describes RFXAP
      as an "associated protein" of the RFX DNA binding complex, not a
      DNA-binding protein itself. The UniProt KW:DNA-binding annotation
      that generated this IEA is erroneous and should be corrected at the
      source.
    supported_by:
      - reference_id: PMID:9806546
        supporting_text: "RFX5 and RFXAP are two subunits of RFX, a multi-protein complex that binds the X box motif of MHC-II promoters"
      - reference_id: PMID:20732328
        supporting_text: "RFXAP(C) is unstructured in the absence of RFX5(N) but adopts a regular structure in the RFX5(N)(2)-RFXAP(C) complex"

- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      IEA annotation for nuclear localization is correct but redundant with
      the IBA and IDA annotations for the same term.
    action: ACCEPT
    reason: >-
      Nuclear localization is correct for RFXAP. The IEA provides additional
      automated confirmation of what is already established by experimental
      evidence.
    supported_by:
      - reference_id: PMID:10938133
        supporting_text: "inherited mutations in the genes encoding the heterotrimeric transcription factor RFX"

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10938133
  review:
    summary: >-
      Protein binding annotation based on interaction studies. This is
      uninformative without specifying what proteins are bound.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GO guidelines discourage generic "protein binding" annotations as they
      provide no specific functional information. RFXAP's actual function
      involves specific binding to RFX5 and RFXANK to form the RFX complex.
      More informative annotations should specify the actual binding partners
      and functional context.
    supported_by:
      - reference_id: PMID:10938133
        supporting_text: "The results identified specific domains within each of the three RFX subunits that were necessary for RFX complex formation"

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20732328
  review:
    summary: >-
      Protein binding annotation from structural study of RFX5-RFXAP
      interaction. Uninformative as a generic annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      This study provides detailed structural information about the
      RFX5(N)2-RFXAP(C) complex. The generic "protein binding" annotation
      fails to capture this specificity. A more appropriate annotation
      would be to a term describing RFX5 binding or transcription factor
      complex assembly.
    supported_by:
      - reference_id: PMID:20732328
        supporting_text: "Two RFX5 molecules and one RFXAP molecule assemble in the cytoplasm prior to nuclear localization"

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25752541
  review:
    summary: >-
      Protein binding from large-scale interaction study (ANKRA2 study). Generic and
      uninformative. The interaction partner is RFXANK (O14593) which is well-established
      from low-throughput studies (PMID:10938133).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding provides no specific functional insight.
      This appears to be from a high-throughput study. While the RFXAP-RFXANK
      interaction is genuine and critical for RFX complex function, the generic
      GO:0005515 annotation fails to capture the functional significance.
    supported_by:
      - reference_id: PMID:10938133
        supporting_text: "The results identified specific domains within each of the three RFX subunits that were necessary for RFX complex formation"

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26496610
  review:
    summary: >-
      Protein binding from large-scale interactome study. The interaction partner is RFX5
      (P48382). This interaction is well-established from structural studies (PMID:20732328).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding provides no specific functional insight.
      High-throughput interactome data. While the RFXAP-RFX5 interaction is genuine
      and structurally characterized, the generic annotation should be replaced with
      more specific functional terms.
    supported_by:
      - reference_id: PMID:20732328
        supporting_text: "Two RFX5 molecules and one RFXAP molecule assemble in the cytoplasm prior to nuclear localization"

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  review:
    summary: >-
      Protein binding from human interactome architecture study. The interaction
      partner is RFX5 (P48382), consistent with the RFX complex structure.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding provides no specific functional insight.
      High-throughput interactome data. The RFXAP-RFX5 interaction is genuine
      but better captured by GO:0090575 (RNA polymerase II transcription
      regulator complex) which specifies the functional context.
    supported_by:
      - reference_id: PMID:20732328
        supporting_text: "RFXAP(C) is unstructured in the absence of RFX5(N) but adopts a regular structure in the RFX5(N)(2)-RFXAP(C) complex"

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  review:
    summary: >-
      Protein binding from dual proteome interactome study. Multiple interaction
      partners detected: RFXANK (O14593) and RFX5 (P48382), consistent with
      the known RFX complex architecture.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding provides no specific functional insight.
      High-throughput interactome data. The interactions with RFXANK and RFX5
      are genuine and represent the core RFX complex components, but the
      generic annotation fails to capture functional significance.
    supported_by:
      - reference_id: PMID:9806546
        supporting_text: "RFX5 and RFXAP are two subunits of RFX, a multi-protein complex that binds the X box motif of MHC-II promoters"

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  review:
    summary: >-
      Protein binding from multimodal cell maps study. The interaction partner
      is RFXANK (O14593), consistent with the RFX complex.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding provides no specific functional insight.
      High-throughput interactome data. The RFXAP-RFXANK interaction is
      well-established as essential for RFX complex function but should be
      captured by more specific annotations.
    supported_by:
      - reference_id: PMID:9806546
        supporting_text: "Its interaction with RFX5 and RFXAP is essential for binding of the RFX complex to MHC-II promoters"

- term:
    id: GO:0016607
    label: nuclear speck
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: >-
      Nuclear speck localization from HPA immunofluorescence data. May
      represent a subset of the protein's localization.
    action: KEEP_AS_NON_CORE
    reason: >-
      Nuclear speck localization is based on immunofluorescence data from
      the Human Protein Atlas. While this may represent genuine localization,
      the primary functional localization of RFXAP is at MHC class II gene
      promoters where it functions in the RFX complex. Nuclear speck
      localization may represent storage or processing rather than active
      function.

- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:10938133
  review:
    summary: >-
      Nuclear localization established by direct assay in the DeSandro et al.
      study of BLS factors.
    action: ACCEPT
    reason: >-
      Direct experimental evidence for nuclear localization. Essential for
      RFXAP's function in the nuclear RFX transcription regulatory complex.
    supported_by:
      - reference_id: PMID:10938133
        supporting_text: "The bare lymphocyte syndrome, a severe combined immunodeficiency due to loss of major histocompatibility complex (MHC) class II gene expression"

- term:
    id: GO:0045348
    label: positive regulation of MHC class II biosynthetic process
  evidence_type: NAS
  original_reference_id: PMID:10938133
  review:
    summary: >-
      RFXAP is essential for MHC class II gene expression. Mutations in
      RFXAP cause MHC class II deficiency (bare lymphocyte syndrome).
      This is a core biological process annotation. Deep research confirms
      RFXAP mutations found in BLS II patients (3/18 in Iranian cohort,
      PMID:37584719) with complete loss of HLA-DR expression.
    action: ACCEPT
    reason: >-
      RFXAP is absolutely required for MHC class II expression. This is
      demonstrated by the disease phenotype in patients with RFXAP mutations
      and by complementation studies showing restoration of MHC class II
      expression upon RFXAP transfection.
    additional_reference_ids:
      - file:human/RFXAP/RFXAP-deep-research-falcon.md
      - PMID:37584719
    supported_by:
      - reference_id: PMID:9118943
        supporting_text: "Complementation of the 6.1.6 and DA cell lines by transfection with RFXAP fully restores expression of all endogenous MHC-II genes in vivo, demonstrating that RFXAP is a novel essential MHC-II regulatory gene"
      - reference_id: PMID:10938133
        supporting_text: "loss of major histocompatibility complex (MHC) class II gene expression, is caused by inherited mutations in the genes encoding the heterotrimeric transcription factor RFX"
      - reference_id: file:human/RFXAP/RFXAP-deep-research-falcon.md
        supporting_text: "Disruption of any RFX subunit--including RFXAP--abolishes MHC-II expression (HLA-DR) on antigen-presenting cells and causes BLS II"

- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IDA
  original_reference_id: PMID:10938133
  review:
    summary: >-
      RFXAP positively regulates transcription of MHC class II genes.
      This is demonstrated by the loss of MHC class II expression when
      RFXAP is mutated and restoration upon complementation.
    action: ACCEPT
    reason: >-
      Core function of RFXAP. The RFX complex activates transcription of
      MHC class II genes. RFXAP is essential for complex assembly and
      therefore for transcriptional activation.
    supported_by:
      - reference_id: PMID:10938133
        supporting_text: "transactivation was dependent on a region of RFX5"

# The contributes_to GO:0000977 annotations - RFXAP does NOT bind DNA
- term:
    id: GO:0000977
    label: RNA polymerase II transcription regulatory region sequence-specific DNA binding
  evidence_type: IDA
  original_reference_id: PMID:9118943
  review:
    summary: >-
      This annotation with 'contributes_to' qualifier attempts to capture
      that RFXAP is part of a DNA-binding complex but does not itself bind
      DNA. However, this is misleading because the term explicitly describes
      sequence-specific DNA binding, which RFXAP does not perform. The
      'contributes_to' qualifier is typically used when a protein is part
      of a complex that has the function, but RFXAP's contribution is
      enabling RFX5's DNA binding through conformational change, not
      through any DNA-binding activity of its own.
    action: MODIFY
    reason: >-
      RFXAP does NOT bind DNA - not even as a contributor. RFX5 is the
      DNA-binding subunit. RFXAP contributes to DNA binding indirectly by
      forming a scaffold with RFXANK that induces a conformational change
      in RFX5 to expose its DNA-binding domain. This is a regulatory
      function, not a DNA-binding function. The correct annotation should
      be to a transcription coactivator or transcription factor complex
      assembly term.
    proposed_replacement_terms:
      - id: GO:0003713
        label: transcription coactivator activity
    supported_by:
      - reference_id: PMID:9806546
        supporting_text: "RFX5 and RFXAP are two subunits of RFX, a multi-protein complex that binds the X box motif of MHC-II promoters"
      - reference_id: PMID:9806546
        supporting_text: "Its interaction with RFX5 and RFXAP is essential for binding of the RFX complex to MHC-II promoters"

- term:
    id: GO:0000977
    label: RNA polymerase II transcription regulatory region sequence-specific DNA binding
  evidence_type: IDA
  original_reference_id: PMID:9806546
  review:
    summary: >-
      Same issue as the PMID:9118943 annotation. RFXAP does not bind DNA.
      The 'contributes_to' qualifier does not fix the fundamental problem
      that this term describes DNA binding, which RFXAP does not perform.
    action: MODIFY
    reason: >-
      RFXAP serves as a scaffolding protein that enables RFX5's DNA binding.
      It does not itself bind DNA or contribute to DNA binding directly.
      Should be annotated to transcription coactivator activity instead.
    proposed_replacement_terms:
      - id: GO:0003713
        label: transcription coactivator activity
    supported_by:
      - reference_id: PMID:9806546
        supporting_text: "RFXANK contains a protein-protein interaction region consisting of three ankyrin repeats. Its interaction with RFX5 and RFXAP is essential for binding of the RFX complex to MHC-II promoters"

# The contributes_to GO:0001228 annotations - THE CORE PROBLEMATIC ANNOTATIONS
- term:
    id: GO:0001228
    label: DNA-binding transcription activator activity, RNA polymerase II-specific
  evidence_type: IDA
  original_reference_id: PMID:9118943
  review:
    summary: >-
      THIS IS THE CORE PROBLEMATIC ANNOTATION. GO:0001228 is "DNA-binding
      transcription activator activity" - by definition, this requires the
      protein to be a DNA-binding transcription factor. RFXAP is NOT a
      DNA-binding protein. Even with the 'contributes_to' qualifier, this
      annotation is incorrect because it causes RFXAP to appear in queries
      for DNA-binding transcription factors (dbTFs). RFXAP is a transcription
      coactivator (coTF), not a dbTF.
    action: MODIFY
    reason: >-
      GO:0001228 explicitly describes "DNA-binding transcription activator
      activity" - the GO definition states this is a "DNA-binding transcription
      factor activity that activates or increases transcription." RFXAP does
      not bind DNA. The DNA-binding subunit of the RFX complex is RFX5.
      RFXAP and RFXANK serve as scaffolding proteins that assemble with RFX5
      and induce a conformational change that exposes RFX5's DNA-binding
      domain. RFXAP should be annotated to GO:0003713 (transcription
      coactivator activity), which correctly describes its function as a
      non-DNA-binding component that activates transcription through a
      DNA-binding transcription factor.
    proposed_replacement_terms:
      - id: GO:0003713
        label: transcription coactivator activity
    additional_reference_ids:
      - PMID:20732328
    supported_by:
      - reference_id: PMID:9118943
        supporting_text: "RFXAP, a novel subunit of the RFX DNA binding complex is mutated in MHC class II deficiency"
      - reference_id: PMID:9806546
        supporting_text: "RFX5 and RFXAP are two subunits of RFX, a multi-protein complex that binds the X box motif of MHC-II promoters"
      - reference_id: PMID:20732328
        supporting_text: "Two RFX5 molecules and one RFXAP molecule assemble in the cytoplasm prior to nuclear localization"

- term:
    id: GO:0001228
    label: DNA-binding transcription activator activity, RNA polymerase II-specific
  evidence_type: IDA
  original_reference_id: PMID:9806546
  review:
    summary: >-
      Same fundamental problem as the PMID:9118943 annotation. RFXAP is
      being incorrectly annotated as a DNA-binding transcription factor
      when it is actually a transcription coactivator.
    action: MODIFY
    reason: >-
      RFXAP does not bind DNA. It is a scaffolding subunit of the RFX
      complex that enables the DNA-binding activity of RFX5. Should be
      annotated to transcription coactivator activity (GO:0003713).
    proposed_replacement_terms:
      - id: GO:0003713
        label: transcription coactivator activity
    supported_by:
      - reference_id: PMID:9806546
        supporting_text: "RFXANK contains a protein-protein interaction region consisting of three ankyrin repeats. Its interaction with RFX5 and RFXAP is essential for binding of the RFX complex to MHC-II promoters"

- term:
    id: GO:0090575
    label: RNA polymerase II transcription regulator complex
  evidence_type: IPI
  original_reference_id: PMID:9118943
  review:
    summary: >-
      RFXAP is part of the RFX transcription regulatory complex. This
      cellular component annotation is accurate.
    action: ACCEPT
    reason: >-
      RFXAP is a bona fide component of the RFX transcription regulator
      complex, as demonstrated by co-immunoprecipitation and structural
      studies. This is a core annotation.
    supported_by:
      - reference_id: PMID:9118943
        supporting_text: "RFXAP, a novel subunit of the RFX DNA binding complex is mutated in MHC class II deficiency"
      - reference_id: PMID:20732328
        supporting_text: "The mammalian immune response is mediated by a heterotetrameric transcriptional control complex, called regulatory factor X (RFX)"

- term:
    id: GO:0090575
    label: RNA polymerase II transcription regulator complex
  evidence_type: IPI
  original_reference_id: PMID:9806546
  review:
    summary: >-
      RFXAP is part of the RFX complex. Duplicate annotation from different
      publication but still valid.
    action: ACCEPT
    reason: >-
      Confirmed component of the RFX transcription regulator complex from
      additional publication.
    supported_by:
      - reference_id: PMID:9806546
        supporting_text: "RFX5 and RFXAP are two subunits of RFX, a multi-protein complex"

- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IMP
  original_reference_id: PMID:9118943
  review:
    summary: >-
      Mutant phenotype demonstrates RFXAP is required for transcriptional
      activation of MHC class II genes.
    action: ACCEPT
    reason: >-
      IMP evidence from cell lines with RFXAP mutations showing loss of
      MHC class II gene expression, and complementation restoring
      expression. Core biological process function.
    supported_by:
      - reference_id: PMID:9118943
        supporting_text: "Complementation of the 6.1.6 and DA cell lines by transfection with RFXAP fully restores expression of all endogenous MHC-II genes in vivo"

- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IDA
  original_reference_id: PMID:9806546
  review:
    summary: >-
      Direct assay evidence for positive regulation of transcription.
      Duplicate of other evidence codes but valid.
    action: ACCEPT
    reason: >-
      Additional experimental support for RFXAP's role in transcriptional
      activation.
    supported_by:
      - reference_id: PMID:9806546
        supporting_text: "RFXANK restores MHC-II expression in cell lines from patients in group B and is mutated in these patients"

# Proposed new annotation based on review
- term:
    id: GO:0003713
    label: transcription coactivator activity
  evidence_type: IDA
  original_reference_id: PMID:9118943
  review:
    summary: >-
      NEW ANNOTATION. RFXAP should be annotated to transcription coactivator
      activity (GO:0003713) instead of DNA-binding transcription activator
      activity (GO:0001228). RFXAP functions as a non-DNA-binding component
      of the RFX complex that activates transcription through its interaction
      with the DNA-binding transcription factor RFX5.
    action: NEW
    reason: >-
      GO:0003713 (transcription coactivator activity) correctly describes
      RFXAP's function. The GO definition states this is "a transcription
      coregulator activity that activates or increases the transcription
      of specific gene sets via binding to a DNA-binding transcription
      factor." RFXAP binds to RFX5 (the DNA-binding transcription factor)
      and enables transcriptional activation of MHC class II genes. This
      is the appropriate molecular function annotation for RFXAP.
    supported_by:
      - reference_id: PMID:9118943
        supporting_text: "RFXAP, a novel subunit of the RFX DNA binding complex is mutated in MHC class II deficiency"
      - reference_id: PMID:10938133
        supporting_text: "transactivation was dependent on a region of RFX5"
      - reference_id: PMID:20732328
        supporting_text: "RFXAP(C) is unstructured in the absence of RFX5(N) but adopts a regular structure in the RFX5(N)(2)-RFXAP(C) complex"

references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings:
    - statement: IBA annotations for nuclear localization and regulation of transcription are appropriate for RFXAP

- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings:
    - statement: HPA immunofluorescence shows nuclear speck localization

- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings:
    - statement: IEA for DNA binding is INCORRECT and should be removed
    - statement: IEA for nucleus is correct but redundant with experimental evidence

- id: PMID:9118943
  title: >-
    RFXAP, a novel subunit of the RFX DNA binding complex is mutated in MHC
    class II deficiency
  findings:
    - statement: RFXAP is a novel subunit of the RFX complex, distinct from RFX5
      supporting_text: "RFXAP, a novel subunit of the RFX DNA binding complex is mutated in MHC class II deficiency"
    - statement: RFXAP is mutated in MHC class II deficiency complementation group D
      supporting_text: "RFXAP is mutated in the 6.1.6 cell line (group D), as well as in an MHC-II deficiency patient (DA)"
    - statement: Complementation with RFXAP restores MHC class II gene expression
      supporting_text: "Complementation of the 6.1.6 and DA cell lines by transfection with RFXAP fully restores expression of all endogenous MHC-II genes in vivo"

- id: PMID:9806546
  title: >-
    A gene encoding a novel RFX-associated transactivator is mutated in the
    majority of MHC class II deficiency patients
  findings:
    - statement: RFX5 and RFXAP are two subunits of the RFX complex
      supporting_text: "RFX5 and RFXAP are two subunits of RFX, a multi-protein complex that binds the X box motif of MHC-II promoters"
    - statement: RFX complex binds the X box motif of MHC-II promoters
      supporting_text: "a multi-protein complex that binds the X box motif of MHC-II promoters"
    - statement: RFXANK interaction with RFX5 and RFXAP is essential for DNA binding
      supporting_text: "Its interaction with RFX5 and RFXAP is essential for binding of the RFX complex to MHC-II promoters"

- id: PMID:10938133
  title: Associations and interactions between bare lymphocyte syndrome factors
  findings:
    - statement: Identified specific domains required for RFX complex formation
      supporting_text: "The results identified specific domains within each of the three RFX subunits that were necessary for RFX complex formation"
    - statement: DNA binding is dependent on RFX complex formation
      supporting_text: "DNA binding was dependent on RFX complex formation"
    - statement: Transactivation is dependent on a region of RFX5
      supporting_text: "transactivation was dependent on a region of RFX5"

- id: PMID:20732328
  title: >-
    Solution structure of the heterotrimeric complex between the interaction
    domains of RFX5 and RFXAP from the RFX gene regulatory complex
  findings:
    - statement: RFXAP C-terminal domain is unstructured alone but folds upon RFX5 binding
      supporting_text: "RFXAP(C) is unstructured in the absence of RFX5(N) but adopts a regular structure in the RFX5(N)(2)-RFXAP(C) complex"
    - statement: Two RFX5 molecules and one RFXAP assemble in cytoplasm before nuclear localization
      supporting_text: "Two RFX5 molecules and one RFXAP molecule assemble in the cytoplasm prior to nuclear localization"
    - statement: RFXAP provides structural scaffolding for complex assembly
      supporting_text: "The mammalian immune response is mediated by a heterotetrameric transcriptional control complex, called regulatory factor X (RFX)"

- id: PMID:25752541
  title: Ankyrin repeats of ANKRA2 recognize a PxLPxL motif on the 3M syndrome protein CCDC8
  findings: []

- id: PMID:26496610
  title: A human interactome in three quantitative dimensions organized by stoichiometries and abundances
  findings: []

- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease networks
  findings: []

- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome
  findings: []

- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics
  findings: []

core_functions:
  - description: >-
      RFXAP is a scaffolding subunit of the RFX transcription regulatory
      complex that is essential for MHC class II gene expression
    molecular_function:
      id: GO:0003713
      label: transcription coactivator activity
    directly_involved_in:
      - id: GO:0045348
        label: positive regulation of MHC class II biosynthetic process
    locations:
      - id: GO:0005634
        label: nucleus
    in_complex:
      id: GO:0090575
      label: RNA polymerase II transcription regulator complex
    supported_by:
      - reference_id: PMID:9118943
        supporting_text: "RFXAP, a novel subunit of the RFX DNA binding complex is mutated in MHC class II deficiency"
      - reference_id: PMID:20732328
        supporting_text: "RFXAP(C) is unstructured in the absence of RFX5(N) but adopts a regular structure in the RFX5(N)(2)-RFXAP(C) complex"

proposed_new_terms: []

suggested_questions:
  - question: >-
      Should the 'contributes_to' qualifier be used to annotate scaffolding
      subunits to DNA-binding terms when they enable but do not perform DNA
      binding? The current annotation uses 'contributes_to' for GO:0001228 and
      GO:0000977, but this may be misleading as RFXAP does not bind DNA at all.
      The 'contributes_to' qualifier is typically used when a protein is part
      of a complex that has the function, not when the protein enables a
      different subunit to perform the function.
  - question: >-
      Should RFXANK also be reviewed for similar annotation issues as RFXAP?
      RFXANK is the other scaffolding subunit of the RFX complex and likely
      has similar incorrect annotations to DNA-binding terms.

suggested_experiments: []