mex-5

id: Q9XUB2
gene_symbol: mex-5
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:6239
  label: Caenorhabditis elegans
description: MEX-5 is a CCCH-type tandem zinc finger RNA-binding protein that is essential
  for establishing soma/germline asymmetry in early C. elegans embryos. MEX-5 forms
  an anterior-to-posterior concentration gradient in the one-cell embryo, with high
  concentrations at the anterior, driven by PAR-1-dependent phosphorylation that increases
  its diffusion rate in the posterior. MEX-5 functions by binding mRNA with high affinity
  (Kd ~10 nM) but low sequence specificity, recognizing tracts of 6+ uridines. This
  high-affinity mRNA binding allows MEX-5 to compete with PGL-3 (which binds RNA ~20-fold
  weaker) for mRNA, thereby dissolving P granules in the anterior cytoplasm and promoting
  their posterior localization through an mRNA competition mechanism. MEX-5 works
  redundantly with the nearly identical protein MEX-6. MEX-5 is also regulated by
  polo kinases (PLK-1, PLK-2) through binding to phosphorylated T186 (primed by MBK-2/DYRK2),
  which is important for its function in embryonic polarity.
existing_annotations:
- term:
    id: GO:0035925
    label: mRNA 3'-UTR AU-rich region binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: MEX-5 is a CCCH tandem zinc finger protein homologous to tristetraprolin
      (TTP/ZFP36) family members that bind AU-rich elements. However, MEX-5 has diverged
      from mammalian TZF proteins in its RNA specificity. While TTP binds UUAUUUAUU
      elements with high specificity, MEX-5 recognizes poly-uridine tracts (6+ U residues)
      with high affinity but low specificity (PMID:17264081). The IBA annotation may
      be based on phylogenetic inference from the TTP family, but MEX-5 has distinct
      binding specificity.
    action: MODIFY
    reason: MEX-5 does not bind AU-rich elements with the specificity typical of TTP/ZFP36
      family members. PMID:17264081 demonstrates the minimal binding site is a tract
      of six or more uridines and that mutation of a single amino acid in each MEX-5
      zinc finger confers tristetraprolin-like specificity. The divergence of the
      discriminator residue in MEX-5 results in different binding specificity from
      mammalian TZF proteins. A more appropriate term would be poly-pyrimidine tract
      binding (GO:0008187) which is already annotated with IDA evidence.
    proposed_replacement_terms:
    - id: GO:0008187
      label: poly-pyrimidine tract binding
    additional_reference_ids:
    - PMID:17264081
    supported_by:
    - reference_id: PMID:17264081
      supporting_text: The minimal binding site is a tract of six or more uridines
        within a 9-13-nucleotide window. This sequence is remarkably abundant in the
        3'-untranslated region of C. elegans transcripts, demonstrating that MEX-5
        alone cannot specify mRNA target selection. In contrast, human TZF homologs
        tristetraprolin and ERF-2 bind with high specificity to UUAUUUAUU elements.
- term:
    id: GO:0000289
    label: nuclear-transcribed mRNA poly(A) tail shortening
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: This annotation is derived from phylogenetic inference based on homology
      to TTP/ZFP36 family members, which are well-established to promote mRNA deadenylation.
      However, there is no direct evidence that MEX-5 promotes poly(A) tail shortening
      in C. elegans. MEX-5's primary function appears to be competing with PGL-3 for
      mRNA binding to regulate P granule formation, not mRNA decay.
    action: MARK_AS_OVER_ANNOTATED
    reason: While MEX-5 is homologous to TTP/ZFP36 family members that promote mRNA
      deadenylation, the literature on MEX-5 focuses on its role in P granule dissolution
      via mRNA competition (PMID:27594427) and embryonic polarity (PMID:10882103),
      not mRNA decay. MEX-5 has divergent RNA binding specificity from its mammalian
      homologs. Without direct experimental evidence for deadenylation activity, this
      represents an over-annotation based on family function.
    supported_by:
    - reference_id: PMID:27594427
      supporting_text: we show that competition between PGL-3 and MEX-5 for mRNA can
        regulate the formation of PGL-3 droplets.
- term:
    id: GO:0000900
    label: mRNA regulatory element binding translation repressor activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: MEX-5 binds mRNA and is involved in regulating translation of germline
      proteins through its localization to the anterior. The IBA annotation suggests
      translation repressor activity based on phylogenetic inference. MEX-5 does affect
      expression of germline proteins in the anterior, but the mechanism involves
      mRNA competition with PGL-3 and P granule dissolution rather than direct translation
      repression.
    action: UNDECIDED
    reason: While MEX-5 inhibits expression of germline proteins in the anterior (PMID:10882103),
      the mechanism by which it does so is primarily through competing with PGL-3
      for mRNA to dissolve P granules (PMID:27594427), rather than direct translation
      repression. MEX-5 may contribute to translation regulation indirectly, but there
      is no direct evidence that it functions as a translation repressor. This annotation
      requires further investigation.
    supported_by:
    - reference_id: PMID:10882103
      supporting_text: Ectopic expression of MEX-5 is sufficient to inhibit the expression
        of germline proteins, suggesting that MEX-5 functions to inhibit anterior
        expression of the germline proteins.
    - reference_id: PMID:27594427
      supporting_text: we show that competition between PGL-3 and MEX-5 for mRNA can
        regulate the formation of PGL-3 droplets.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: MEX-5 is a cytoplasmic protein that forms a concentration gradient enriched
      in the anterior of the early embryo. The cytosol annotation is consistent with
      experimental data showing cytoplasmic localization (PMID:10882103, PMID:18199581).
    action: ACCEPT
    reason: Cytosol is an appropriate term for MEX-5. MEX-5 is asymmetrically localized
      in the cytoplasm with enrichment in the anterior. UniProt confirms cytoplasmic
      localization based on multiple publications.
    supported_by:
    - reference_id: PMID:10882103
      supporting_text: MEX-5 is a novel, cytoplasmic protein that is localized through
        PAR activities to the anterior pole of the 1-cell stage embryo.
    - reference_id: PMID:18199581
      supporting_text: These polo kinases are asymmetrically localized along the anteroposterior
        axis of newly fertilized C. elegans embryos in a pattern identical to that
        of MEX-5 and MEX-6.
- term:
    id: GO:0160134
    label: protein-RNA sequence-specific adaptor activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: This annotation suggests MEX-5 functions as an adaptor between specific
      RNA sequences and proteins. While MEX-5 binds mRNA and interacts with proteins
      like PLK-1/PLK-2, its RNA binding is NOT sequence-specific - it binds poly-U
      tracts with high affinity but low specificity (PMID:17264081).
    action: MODIFY
    reason: MEX-5 does not have sequence-specific RNA binding. PMID:17264081 clearly
      demonstrates that MEX-5 recognizes linear RNA sequences with high affinity but
      low specificity. The term "sequence-specific" in GO:0160134 does not apply to
      MEX-5's promiscuous binding to any poly-U tract. If an adaptor function term
      is needed, it should not include "sequence-specific."
    proposed_replacement_terms:
    - id: GO:0003729
      label: mRNA binding
    additional_reference_ids:
    - PMID:17264081
    supported_by:
    - reference_id: PMID:17264081
      supporting_text: Here we show that the TZF protein MEX-5, a primary anterior
        determinant, is an RNA-binding protein that recognizes linear RNA sequences
        with high affinity but low specificity.
- term:
    id: GO:0003677
    label: DNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: This annotation is inferred from the UniProt keyword "DNA-binding" based
      on the presence of zinc finger domains. However, MEX-5 contains CCCH-type zinc
      fingers which are RNA-binding domains, not DNA-binding domains. The experimental
      literature demonstrates MEX-5 is an RNA-binding protein, not a DNA-binding protein.
    action: REMOVE
    reason: CCCH-type zinc fingers are RNA-binding domains, not DNA-binding domains.
      All experimental studies characterize MEX-5 as an RNA-binding protein (PMID:17264081,
      PMID:27594427). The UniProt keyword inference is incorrect for this protein
      family.
    supported_by:
    - reference_id: PMID:17264081
      supporting_text: In Caenorhabditis elegans, a gradient of CCCH tandem zinc finger
        (TZF) proteins coordinates axis polarization and germline differentiation.
        These proteins govern expression from maternal mRNAs by an unknown mechanism.
        Here we show that the TZF protein MEX-5, a primary anterior determinant, is
        an RNA-binding protein
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: MEX-5 is well-established as an RNA-binding protein through its CCCH
      tandem zinc fingers. Experimental studies demonstrate high-affinity mRNA binding
      with Kd ~10 nM (PMID:17264081).
    action: ACCEPT
    reason: RNA binding is a core function of MEX-5, extensively documented experimentally.
      MEX-5 binds mRNA with high affinity to compete with PGL-3 for mRNA (PMID:27594427).
    supported_by:
    - reference_id: PMID:17264081
      supporting_text: Here we show that the TZF protein MEX-5, a primary anterior
        determinant, is an RNA-binding protein that recognizes linear RNA sequences
        with high affinity but low specificity.
    - reference_id: PMID:27594427
      supporting_text: we show that competition between PGL-3 and MEX-5 for mRNA can
        regulate the formation of PGL-3 droplets.
- term:
    id: GO:0003729
    label: mRNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: mRNA binding is a core function of MEX-5, demonstrated by biochemical
      studies showing high-affinity binding to mRNA (PMID:17264081, PMID:27594427).
      InterPro-based inference is correct for this protein.
    action: ACCEPT
    reason: This is a well-supported annotation. MEX-5 binds mRNA with high affinity
      through its tandem CCCH zinc fingers.
    supported_by:
    - reference_id: PMID:17264081
      supporting_text: Here we show that the TZF protein MEX-5, a primary anterior
        determinant, is an RNA-binding protein that recognizes linear RNA sequences
        with high affinity but low specificity.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Cytoplasmic localization is well-established for MEX-5 through multiple
      experimental studies. MEX-5 forms an anterior-enriched gradient in the cytoplasm.
    action: ACCEPT
    reason: This is correct. MEX-5 is localized to the cytoplasm, with asymmetric
      enrichment in the anterior (PMID:10882103, PMID:18199581).
    supported_by:
    - reference_id: PMID:10882103
      supporting_text: MEX-5 is a novel, cytoplasmic protein that is localized through
        PAR activities to the anterior pole of the 1-cell stage embryo.
- term:
    id: GO:0008270
    label: zinc ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: MEX-5 contains two CCCH-type zinc finger domains (positions 270-299 and
      314-344 per UniProt), which coordinate zinc ions to form the RNA-binding structure.
    action: ACCEPT
    reason: Zinc binding is intrinsic to the CCCH zinc finger fold. The two C3H1-type
      zinc fingers are annotated in UniProt and are essential for MEX-5's RNA-binding
      function.
- term:
    id: GO:0017148
    label: negative regulation of translation
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  review:
    summary: This annotation is inferred from GO:0000900 (mRNA regulatory element
      binding translation repressor activity). While MEX-5 does inhibit expression
      of germline proteins in the anterior, this appears to be primarily through P
      granule dissolution via mRNA competition rather than direct translation repression.
    action: UNDECIDED
    reason: The inference is based on GO:0000900 which is itself questionable. MEX-5
      affects germline protein expression but the mechanism may be through P granule
      organization rather than direct translation regulation. Needs direct experimental
      evidence for translation repression activity.
    supported_by:
    - reference_id: PMID:10882103
      supporting_text: Ectopic expression of MEX-5 is sufficient to inhibit the expression
        of germline proteins, suggesting that MEX-5 functions to inhibit anterior
        expression of the germline proteins.
- term:
    id: GO:0043186
    label: P granule
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: This IEA annotation suggests MEX-5 is located in P granules. However,
      MEX-5 is primarily localized to the anterior cytoplasm where P granules are
      absent/dissolved. MEX-5 dissolves P granules rather than residing in them.
    action: MODIFY
    reason: MEX-5 is not a resident P granule component - it actively dissolves P
      granules by competing for mRNA (PMID:27594427). MEX-5 is enriched in the anterior
      where P granules are dissolved. The "located_in P granule" annotation is misleading.
      MEX-5 may transiently interact with P granules but is functionally opposed to
      them.
    proposed_replacement_terms:
    - id: GO:1903864
      label: P granule disassembly
    additional_reference_ids:
    - PMID:27594427
    supported_by:
    - reference_id: PMID:27594427
      supporting_text: We conclude that gradients of polarity proteins can position
        RNP granules during development by using RNA competition to regulate local
        phase separation.
- term:
    id: GO:0046872
    label: metal ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: MEX-5 contains CCCH zinc finger domains that bind zinc ions. Metal ion
      binding is a valid but generic annotation.
    action: ACCEPT
    reason: This is correct - the CCCH zinc fingers coordinate zinc ions. GO:0008270
      (zinc ion binding) is more specific and also annotated.
- term:
    id: GO:0019901
    label: protein kinase binding
  evidence_type: IPI
  original_reference_id: PMID:18199581
  review:
    summary: PMID:18199581 demonstrates that MEX-5 (when phosphorylated on T186) binds
      to polo kinases PLK-1 and PLK-2 via their polo box domains. This is a direct
      experimental observation.
    action: ACCEPT
    reason: PMID:18199581 provides direct experimental evidence for MEX-5 binding
      to polo kinases. This interaction is functionally significant for embryonic
      polarity.
    supported_by:
    - reference_id: PMID:18199581
      supporting_text: We show that polo kinases, via their polo box domains, bind
        to and regulate the activity of two key polarity proteins, MEX-5 and MEX-6.
- term:
    id: GO:0019904
    label: protein domain specific binding
  evidence_type: IPI
  original_reference_id: PMID:18199581
  review:
    summary: MEX-5 binds specifically to the polo box domains of PLK-1 and PLK-2 when
      phosphorylated at T186. This is a legitimate domain-specific interaction.
    action: ACCEPT
    reason: PMID:18199581 demonstrates that MEX-5 binds to polo kinases via their
      polo box domains, supporting the protein domain specific binding annotation.
    supported_by:
    - reference_id: PMID:18199581
      supporting_text: polo kinases, via their polo box domains, bind to and regulate
        the activity of two key polarity proteins, MEX-5 and MEX-6.
- term:
    id: GO:0032880
    label: regulation of protein localization
  evidence_type: IMP
  original_reference_id: PMID:18199581
  review:
    summary: MEX-5 regulates the asymmetric localization of multiple proteins including
      PLK-1, PIE-1, MEX-1, and POS-1 during early embryogenesis. This is extensively
      documented.
    action: ACCEPT
    reason: This is a core function of MEX-5. MEX-5 establishes asymmetric distribution
      of germline proteins to the posterior by inhibiting their expression/localization
      in the anterior (PMID:10882103, PMID:18199581).
    supported_by:
    - reference_id: PMID:10882103
      supporting_text: This network is required for subsequent asymmetries in the
        expression patterns of several proteins that are encoded by nonlocalized,
        maternally expressed mRNAs.
    - reference_id: PMID:18199581
      supporting_text: This asymmetric localization of polo kinases depends on MEX-5
        and MEX-6, as well as genes regulating MEX-5 and MEX-6 asymmetry.
- term:
    id: GO:0032880
    label: regulation of protein localization
  evidence_type: IGI
  original_reference_id: PMID:18199581
  review:
    summary: Same term as above but with IGI evidence code (genetic interaction).
      MEX-5 and MEX-6 work redundantly to regulate protein localization.
    action: ACCEPT
    reason: The redundant function with MEX-6 is well-documented. MEX-5/MEX-6 double
      knockdown shows stronger phenotypes than single knockdowns.
    supported_by:
    - reference_id: PMID:10882103
      supporting_text: We provide evidence that two nearly identical genes, mex-5
        and mex-6, link PAR asymmetry to those subsequent protein asymmetries.
- term:
    id: GO:0003730
    label: mRNA 3'-UTR binding
  evidence_type: IDA
  original_reference_id: PMID:17264081
  review:
    summary: PMID:17264081 demonstrates that MEX-5 binds to 3'-UTR sequences containing
      poly-U tracts. This is direct experimental evidence for 3'-UTR binding.
    action: ACCEPT
    reason: PMID:17264081 shows MEX-5 recognizes poly-U tracts that are abundant in
      3'-UTRs. The binding specificity studies were performed with RNA sequences.
    supported_by:
    - reference_id: PMID:17264081
      supporting_text: This sequence is remarkably abundant in the 3'-untranslated
        region of C. elegans transcripts
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:10882103
  review:
    summary: PMID:10882103 establishes that MEX-5 is a cytoplasmic protein localized
      to the anterior of the 1-cell embryo. This is primary experimental evidence.
    action: ACCEPT
    reason: This is the original study characterizing MEX-5 localization. Direct observation
      of cytoplasmic localization.
    supported_by:
    - reference_id: PMID:10882103
      supporting_text: MEX-5 is a novel, cytoplasmic protein that is localized through
        PAR activities to the anterior pole of the 1-cell stage embryo.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:12588843
  review:
    summary: PMID:12588843 confirms cytoplasmic localization of MEX-5 using GFP fusions
      and time-lapse microscopy during embryo polarization.
    action: ACCEPT
    reason: Additional experimental confirmation of cytoplasmic localization with
      detailed localization dynamics.
    supported_by:
    - reference_id: PMID:12588843
      supporting_text: Using time-lapse microscopy and GFP fusions, we have analyzed
        the localization dynamics of PAR-2, PAR-6, MEX-5, MEX-6 and PIE-1 in wild-type
        and mutant embryos.
- term:
    id: GO:0008187
    label: poly-pyrimidine tract binding
  evidence_type: IDA
  original_reference_id: PMID:17264081
  review:
    summary: PMID:17264081 directly demonstrates that MEX-5 recognizes poly-uridine
      tracts (6+ U residues) as its binding site. This is high-quality experimental
      evidence for poly- pyrimidine tract binding.
    action: ACCEPT
    reason: This is a core molecular function of MEX-5, directly demonstrated by biochemical
      studies. MEX-5 binds poly-U with high affinity (Kd ~10 nM).
    supported_by:
    - reference_id: PMID:17264081
      supporting_text: The minimal binding site is a tract of six or more uridines
        within a 9-13-nucleotide window.
- term:
    id: GO:0043186
    label: P granule
  evidence_type: IDA
  original_reference_id: PMID:12588843
  review:
    summary: PMID:12588843 may show MEX-5 association with P granules, but the functional
      relationship is that MEX-5 dissolves P granules. The "located_in" qualifier
      is problematic because MEX-5 is enriched in regions where P granules are absent.
    action: MODIFY
    reason: While MEX-5 may transiently interact with or be detected near P granules
      during polarization, its primary functional relationship is to dissolve P granules
      by competing for mRNA (PMID:27594427). The annotation should reflect MEX-5's
      role in P granule disassembly rather than stable localization.
    proposed_replacement_terms:
    - id: GO:1903864
      label: P granule disassembly
    additional_reference_ids:
    - PMID:27594427
    supported_by:
    - reference_id: PMID:27594427
      supporting_text: MEX-5 can regulate PGL-3 drop formation by competing with PGL-3
        for mRNA binding.
- term:
    id: GO:0005813
    label: centrosome
  evidence_type: IDA
  original_reference_id: PMID:10882103
  review:
    summary: PMID:10882103 reports centrosomal localization of MEX-5. This is experimental
      observation but the primary localization of MEX-5 is in the anterior cytoplasm.
    action: KEEP_AS_NON_CORE
    reason: Centrosomal localization may be observed but is not the primary functional
      localization of MEX-5. The core localization is the anterior cytoplasm where
      MEX-5 forms its concentration gradient. This annotation can be kept but should
      not be considered a core function.
    supported_by:
    - reference_id: PMID:10882103
      supporting_text: MEX-5 is a novel, cytoplasmic protein that is localized through
        PAR activities to the anterior pole of the 1-cell stage embryo.
- term:
    id: GO:1903864
    label: P granule disassembly
  evidence_type: IMP
  original_reference_id: PMID:27594427
  review:
    summary: PMID:27594427 demonstrates that MEX-5 dissolves P granules by competing
      with PGL-3 for mRNA binding. This is a core function of MEX-5 and should be
      annotated.
    action: NEW
    reason: P granule disassembly is a key function of MEX-5. The protein competes
      with PGL-3 for mRNA with ~20-fold higher affinity, thereby preventing P granule
      assembly in the anterior.
    supported_by:
    - reference_id: PMID:27594427
      supporting_text: In this model, MEX-5 influences the demixing of PGL-3 and mRNA
        by depleting the local free mRNA concentration.
- term:
    id: GO:0008595
    label: anterior/posterior axis specification, embryo
  evidence_type: IMP
  original_reference_id: PMID:10882103
  review:
    summary: MEX-5 is essential for establishing anterior/posterior asymmetry in early
      C. elegans embryos, functioning downstream of PAR proteins to distribute germline
      determinants.
    action: NEW
    reason: A/P axis specification is a core biological process for MEX-5. The protein
      links PAR polarity to downstream protein asymmetries (PMID:10882103).
    supported_by:
    - reference_id: PMID:10882103
      supporting_text: We provide evidence that two nearly identical genes, mex-5
        and mex-6, link PAR asymmetry to those subsequent protein asymmetries.
    - reference_id: PMID:12588843
      supporting_text: Polarization of the C. elegans zygote along the anterior-posterior
        axis depends on cortically enriched (PAR) and cytoplasmic (MEX-5/6) proteins
- term:
    id: GO:0030719
    label: P granule organization
  evidence_type: IMP
  original_reference_id: PMID:27594427
  review:
    summary: MEX-5 regulates P granule organization through its mRNA competition mechanism,
      controlling when and where P granules assemble in the embryo.
    action: NEW
    reason: P granule organization is a core process regulated by MEX-5. The MEX-5
      gradient drives P granule segregation to the posterior.
    supported_by:
    - reference_id: PMID:27594427
      supporting_text: We conclude that gradients of polarity proteins can position
        RNP granules during development by using RNA competition to regulate local
        phase separation.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  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:0000108
  title: Automatic assignment of GO terms using logical inference, based on inter-ontology
    links
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10882103
  title: MEX-5 and MEX-6 function to establish soma/germline asymmetry in early C.
    elegans embryos.
  findings:
  - statement: MEX-5 is a novel cytoplasmic CCCH zinc finger protein
    supporting_text: MEX-5 is a novel, cytoplasmic protein that is localized through
      PAR activities to the anterior pole of the 1-cell stage embryo.
  - statement: MEX-5 localizes to the anterior of 1-cell embryo through PAR activities
    supporting_text: MEX-5 is a novel, cytoplasmic protein that is localized through
      PAR activities to the anterior pole of the 1-cell stage embryo.
  - statement: Localization is reciprocal to posterior germline proteins
    supporting_text: MEX-5 localization is reciprocal to that of a group of posterior-localized
      proteins called germline proteins.
  - statement: Ectopic MEX-5 inhibits germline protein expression
    supporting_text: Ectopic expression of MEX-5 is sufficient to inhibit the expression
      of germline proteins, suggesting that MEX-5 functions to inhibit anterior expression
      of the germline proteins.
  - statement: mex-5 and mex-6 are nearly identical genes with redundant function
    supporting_text: We provide evidence that two nearly identical genes, mex-5 and
      mex-6, link PAR asymmetry to those subsequent protein asymmetries.
- id: PMID:12588843
  title: Polarization of the C. elegans zygote proceeds via distinct establishment
    and maintenance phases.
  findings:
  - statement: MEX-5/6 function during establishment phase of polarity
    supporting_text: The kinase PAR-1 and the CCCH finger proteins MEX-5 and MEX-6
      also function during the establishment phase in a feedback loop to regulate
      growth of the posterior domain.
  - statement: MEX-5/6 participate in feedback loop with PAR-1 to regulate posterior
      domain
    supporting_text: The kinase PAR-1 and the CCCH finger proteins MEX-5 and MEX-6
      also function during the establishment phase in a feedback loop to regulate
      growth of the posterior domain.
  - statement: GFP-tagged MEX-5 shows dynamic cytoplasmic localization
    supporting_text: Using time-lapse microscopy and GFP fusions, we have analyzed
      the localization dynamics of PAR-2, PAR-6, MEX-5, MEX-6 and PIE-1 in wild-type
      and mutant embryos.
- id: PMID:17264081
  title: Molecular basis of RNA recognition by the embryonic polarity determinant
    MEX-5.
  findings:
  - statement: MEX-5 binds RNA with high affinity but low specificity
    supporting_text: Here we show that the TZF protein MEX-5, a primary anterior determinant,
      is an RNA-binding protein that recognizes linear RNA sequences with high affinity
      but low specificity.
  - statement: Minimal binding site is 6+ uridine tract within 9-13 nucleotide window
    supporting_text: The minimal binding site is a tract of six or more uridines within
      a 9-13-nucleotide window.
  - statement: Poly-U tracts abundant in C. elegans 3'-UTRs
    supporting_text: This sequence is remarkably abundant in the 3'-untranslated region
      of C. elegans transcripts
  - statement: MEX-5 differs from TTP/ERF-2 in binding specificity
    supporting_text: In contrast, human TZF homologs tristetraprolin and ERF-2 bind
      with high specificity to UUAUUUAUU elements.
  - statement: Single amino acid mutation confers TTP-like specificity
    supporting_text: We show that mutation of a single amino acid in each MEX-5 zinc
      finger confers tristetraprolin-like specificity to this protein.
- id: PMID:18199581
  title: Polo kinases regulate C. elegans embryonic polarity via binding to DYRK2-primed
    MEX-5 and MEX-6.
  findings:
  - statement: MEX-5 binds PLK-1 and PLK-2 via polo box domains when phosphorylated
      on T186
    supporting_text: We show that polo kinases, via their polo box domains, bind to
      and regulate the activity of two key polarity proteins, MEX-5 and MEX-6.
  - statement: T186 is phosphorylated by MBK-2 (DYRK2 kinase)
    supporting_text: We also show that MBK-2, a developmentally regulated DYRK2 kinase
      activated at meiosis II, primes T(186) for subsequent polo kinase-dependent
      phosphorylation.
  - statement: T186 phosphorylation is essential for polo kinase binding
    supporting_text: We identify an amino acid of MEX-5, T(186), essential for polo
      binding and show that T(186) is important for MEX-5 function in vivo.
  - statement: Polo kinases are asymmetrically localized like MEX-5/6
    supporting_text: These polo kinases are asymmetrically localized along the anteroposterior
      axis of newly fertilized C. elegans embryos in a pattern identical to that of
      MEX-5 and MEX-6.
  - statement: Polo kinase localization depends on MEX-5/6
    supporting_text: This asymmetric localization of polo kinases depends on MEX-5
      and MEX-6, as well as genes regulating MEX-5 and MEX-6 asymmetry.
- id: PMID:27594427
  title: Polar Positioning of Phase-Separated Liquid Compartments in Cells Regulated
    by an mRNA Competition Mechanism.
  findings:
  - statement: P granules are liquid-like phase-separated compartments
    supporting_text: P granules are non-membrane-bound RNA-protein compartments that
      are involved in germline development in C. elegans. They are liquids that condense
      at one end of the embryo by localized phase separation
  - statement: PGL-3 alone can form P granule-like droplets in vitro
    supporting_text: We reconstitute P granule-like droplets in vitro using a single
      protein PGL-3.
  - statement: MEX-5 competes with PGL-3 for mRNA binding
    supporting_text: we show that competition between PGL-3 and MEX-5 for mRNA can
      regulate the formation of PGL-3 droplets.
  - statement: Competition mechanism drives P granule dissolution in anterior
    supporting_text: In this model, MEX-5 influences the demixing of PGL-3 and mRNA
      by depleting the local free mRNA concentration.
  - statement: MEX-5 gradient regulates local phase separation of P granules
    supporting_text: We conclude that gradients of polarity proteins can position
      RNP granules during development by using RNA competition to regulate local phase
      separation.
core_functions:
- description: MEX-5 dissolves P granules in the anterior of early embryos by competing
    with PGL-3 for mRNA binding. MEX-5's high affinity for mRNA compared to PGL-3
    depletes the free mRNA needed for P granule assembly, causing dissolution through
    altered phase separation dynamics.
  molecular_function:
    id: GO:0008187
    label: poly-pyrimidine tract binding
  directly_involved_in:
  - id: GO:1903864
    label: P granule disassembly
  locations:
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: PMID:27594427
    supporting_text: In this model, MEX-5 influences the demixing of PGL-3 and mRNA
      by depleting the local free mRNA concentration.
- description: MEX-5 establishes soma/germline asymmetry by forming an anterior-enriched
    gradient that inhibits germline protein expression in somatic cell precursors.
    This links PAR protein polarity to downstream developmental asymmetries.
  molecular_function:
    id: GO:0003729
    label: mRNA binding
  directly_involved_in:
  - id: GO:0008595
    label: anterior/posterior axis specification, embryo
  - id: GO:0032880
    label: regulation of protein localization
  locations:
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: PMID:10882103
    supporting_text: We provide evidence that two nearly identical genes, mex-5 and
      mex-6, link PAR asymmetry to those subsequent protein asymmetries.
- description: MEX-5 binds mRNA with high affinity but low sequence specificity through
    its CCCH tandem zinc fingers, recognizing tracts of 6+ uridines. This promiscuous
    binding enables competition with other RNA-binding proteins for bulk mRNA.
  molecular_function:
    id: GO:0008187
    label: poly-pyrimidine tract binding
  locations:
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: PMID:17264081
    supporting_text: The minimal binding site is a tract of six or more uridines within
      a 9-13-nucleotide window.
proposed_new_terms: []
suggested_questions:
- question: Does MEX-5 directly repress translation, or is its effect on germline
    protein expression entirely through P granule dissolution?
- question: What is the structural basis for MEX-5's low sequence specificity compared
    to its TTP homologs?
suggested_experiments:
- description: Perform ribosome profiling/Ribo-seq to determine if MEX-5 directly
    affects translation. This would distinguish between MEX-5's proposed translation
    repression activity and its documented mRNA competition function.
  hypothesis: MEX-5 affects germline protein expression through P granule dissolution
    rather than direct translation repression
- description: Perform CLIP-seq to identify MEX-5 RNA targets genome-wide. This would
    validate the low-specificity binding model and identify which mRNAs MEX-5 competes
    for with PGL-3.
  hypothesis: MEX-5 binds promiscuously to most mRNAs containing poly-U tracts
tags:
- caeel-p-granules