id: P42704
gene_symbol: LRPPRC
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  LRPPRC (Leucine-rich PPR motif-containing protein) is a mitochondrial PPR protein
  that functions
  as a key regulator of mitochondrial mRNA metabolism. It forms a stable ribonucleoprotein
  complex
  with SLIRP (SRA stem-loop interacting RNA-binding protein) and performs three core
  functions:
  (1) stabilization of mitochondrial mRNAs by protecting them from 3'-5' exonucleolytic
  degradation
  by the PNPase/SUV3 degradosome, (2) promotion of polyadenylation of mt-mRNAs via
  MTPAP, and
  (3) delivery of mRNAs to the mitoribosome through direct interaction with mS39 and
  mS31.
  Cryo-EM structures (2024) reveal LRPPRC acts as an mRNA "holdase" that maintains
  proper mRNA
  folding for efficient translation. Loss of LRPPRC causes the French-Canadian form
  of Leigh
  syndrome (LSFC) with cytochrome c oxidase deficiency. While predominantly mitochondrial,
  a
  fraction localizes to the nucleus where it may participate in nuclear mRNA export
  via EIF4E.
existing_annotations:
  - term:
      id: GO:0070129
      label: regulation of mitochondrial translation
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        LRPPRC regulates mitochondrial translation through its role in mRNA delivery
        to the mitoribosome.
        Cryo-EM studies (Singh et al., 2024) show LRPPRC-SLIRP docks on the small
        mitoribosomal subunit
        via mS39 and mS31, forming a corridor for mRNA delivery to the decoding center.
        Loss of LRPPRC
        causes transcript-specific translation efficiency changes, with COX1/COX2
        translation reduced
        >2-fold while ND6 translation increases >2-fold (PMID:Singh et al. 2024).
      action: ACCEPT
      reason: >-
        This annotation accurately captures a core function of LRPPRC. The IBA annotation
        is well-supported
        by extensive experimental evidence showing LRPPRC's role in delivering mRNAs
        to the mitoribosome
        and modulating translation efficiency in a transcript-specific manner.
      supported_by:
        - reference_id: file:human/LRPPRC/LRPPRC-deep-research-falcon.md
          supporting_text: "Cryo-EM of human LRPPRC-SLIRP in complex with mRNA and
            the mitoribosome demonstrates direct association of LRPPRC with mS39 and
            mS31, with SLIRP directly holding mRNA; loss of LRPPRC yields transcript-specific
            translation efficiency (TE) changes"
        - reference_id: PMID:22661577
          supporting_text: "In this article, we provide evidence that the LRPPRC/SLIRP
            complex suppresses mRNA degradation mediated by PNPase and SUV3 and promotes
            polyadenylation of mRNA mediated by mitochondrial poly(A) polymerase MTPAP
            in vitro"
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        LRPPRC is predominantly localized to the mitochondrial matrix where it performs
        its core
        functions in mRNA metabolism. Multiple studies confirm mitochondrial localization
        via
        immunofluorescence, subcellular fractionation, and proteomics (PMID:12832482,
        PMID:34800366).
      action: ACCEPT
      reason: >-
        Mitochondrial localization is a core aspect of LRPPRC function and is extensively
        validated
        by multiple experimental approaches. UniProt notes "Seems to be predominantly
        mitochondrial."
      supported_by:
        - reference_id: PMID:12832482
          supporting_text: "The majority of LRP130 proteins are located within mitochondria,
            where they are directly bound to polyadenylated RNAs in vivo"
  - term:
      id: GO:0003730
      label: mRNA 3'-UTR binding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        LRPPRC binds mitochondrial mRNAs; however, mitochondrial mRNAs lack classical
        3'-UTRs.
        LRPPRC-SLIRP binds primarily to coding sequences of mt-mRNAs rather than UTR
        regions.
        The 3'-UTR binding annotation may be more appropriate for nuclear RNA interactions
        or
        reflect ortholog functions in other species.
      action: MODIFY
      reason: >-
        While LRPPRC does bind mRNA, the specific term "mRNA 3'-UTR binding" is misleading
        for
        its primary mitochondrial function where it binds coding sequences. A more
        appropriate
        term would be "mRNA binding" (GO:0003729) which is already annotated with
        IDA evidence.
      proposed_replacement_terms:
        - id: GO:0003729
          label: mRNA binding
      supported_by:
        - reference_id: PMID:22661577
          supporting_text: "The LRPPRC/SLIRP complex recognizes mRNA coding sequences"
        - reference_id: PMID:12832482
          supporting_text: "In vitro, LRP130 binds preferentially to polypyrimidines.
            This RNA-binding activity maps to a domain in its C-terminal region"
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        A fraction of LRPPRC localizes to the nucleus where it participates in mRNA
        export
        via interaction with EIF4E and XPO1/CRM1. Multiple IDA studies confirm nuclear
        localization
        (PMID:12762840, PMID:12832482).
      action: KEEP_AS_NON_CORE
      reason: >-
        Nuclear localization is real but represents a secondary function. The primary
        function
        of LRPPRC is in the mitochondrial matrix. Nuclear localization relates to
        its proposed
        role in mRNA export which is less well-established than its mitochondrial
        functions.
      supported_by:
        - reference_id: PMID:12832482
          supporting_text: "We show here that only a fraction of LRP130 proteins are
            in nuclei and are directly bound in vivo to at least some of the same
            RNA molecules as the nucleocytoplasmic shuttle protein hnRNP A1"
  - term:
      id: GO:0003677
      label: DNA binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        This annotation derives from UniProt keyword mapping. UniProt states LRPPRC
        "Binds
        single-stranded DNA (By similarity)." However, there is no direct experimental
        evidence
        for DNA binding by human LRPPRC. The core function is RNA binding, not DNA
        binding.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        DNA binding is inferred by similarity and not experimentally demonstrated
        for human LRPPRC.
        The protein's established functions are all related to RNA metabolism. This
        annotation
        should be deprioritized as it does not reflect a core or well-established
        function.
      supported_by:
        - reference_id: PMID:12832482
          supporting_text: "LRP130 is a novel type of RNA-binding protein that associates
            with both nuclear and mitochondrial mRNAs"
  - term:
      id: GO:0003723
      label: RNA binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        RNA binding is a core function of LRPPRC, extensively validated by multiple
        experimental
        approaches. LRPPRC binds both mitochondrial and nuclear mRNAs. This IEA annotation
        duplicates well-supported HDA annotations from PMID:22658674 and PMID:22681889.
      action: ACCEPT
      reason: >-
        RNA binding is a fundamental molecular function of LRPPRC. Even though this
        is an IEA
        annotation, it is correct and supported by extensive experimental evidence.
      supported_by:
        - reference_id: PMID:12832482
          supporting_text: "LRP130 is a novel type of RNA-binding protein that associates
            with both nuclear and mitochondrial mRNAs"
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        Duplicate of IBA annotation. Nuclear localization is supported but represents
        a minor fraction of LRPPRC protein.
      action: KEEP_AS_NON_CORE
      reason: >-
        Valid but non-core localization. The majority of LRPPRC is mitochondrial.
      supported_by:
        - reference_id: PMID:12832482
          supporting_text: "only a fraction of LRP130 proteins are in nuclei"
  - term:
      id: GO:0005637
      label: nuclear inner membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: >-
        This annotation derives from UniProt subcellular location mapping. UniProt
        lists
        "Nucleus inner membrane" but the evidence for this specific localization is
        limited.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        While LRPPRC has nuclear localization, specific localization to the nuclear
        inner
        membrane is not well-supported by experimental evidence. This appears to be
        an
        over-specific inference from general nuclear localization data.
  - term:
      id: GO:0005640
      label: nuclear outer membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: >-
        This annotation derives from UniProt subcellular location mapping. One study
        (PMID:15081402) suggested outer nuclear membrane localization, but this is
        not
        the primary or well-established localization.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Nuclear outer membrane localization is mentioned in early literature but not
        confirmed by more recent comprehensive studies. The primary localization is
        mitochondrial matrix.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: >-
        LRPPRC has been detected in the nucleus but specific nucleoplasmic localization
        versus other nuclear compartments is not well-established.
      action: KEEP_AS_NON_CORE
      reason: >-
        Nuclear localization is documented, and nucleoplasm is a reasonable inference
        for the nuclear fraction. Kept as non-core since mitochondrial localization
        is primary.
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        Duplicate of IBA annotation. Mitochondrial localization is the primary and
        best-supported localization for LRPPRC.
      action: ACCEPT
      reason: >-
        This is the core localization for LRPPRC function. Duplicates are acceptable
        when supported by multiple evidence types.
      supported_by:
        - reference_id: PMID:12832482
          supporting_text: "The majority of LRP130 proteins are located within mitochondria"
  - term:
      id: GO:0006914
      label: autophagy
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        This annotation derives from UniProt keyword mapping based on PMID:23822101
        which
        reported LRPPRC suppresses basal autophagy via BCL2 stabilization. However,
        this
        is likely a secondary consequence of mitochondrial dysfunction rather than
        a
        direct function of LRPPRC. The primary role of LRPPRC is in mitochondrial
        mRNA
        metabolism, not autophagy regulation.
      action: REMOVE
      reason: >-
        This is an OVER-ANNOTATION. LRPPRC's core function is in mitochondrial mRNA
        metabolism.
        The reported autophagy suppression (via BCL2/BECN1 interaction) is likely
        an indirect
        effect or artifact of its role in maintaining mitochondrial function. When
        mitochondria
        are dysfunctional due to LRPPRC deficiency, mitophagy may be triggered as
        a secondary
        response. The protein does not function as an autophagy regulator per se.
      additional_reference_ids:
        - PMID:23822101
  - term:
      id: GO:0051028
      label: mRNA transport
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        This annotation derives from UniProt keyword mapping. LRPPRC has been implicated
        in nuclear mRNA export via EIF4E interactions (PMID:19262567, PMID:28325843).
        However, this is a secondary function compared to its mitochondrial role.
      action: KEEP_AS_NON_CORE
      reason: >-
        mRNA transport/export is supported by literature but represents a minor function
        compared to the well-established mitochondrial mRNA metabolism role. The nuclear
        mRNA export function involves only a fraction of LRPPRC protein.
      supported_by:
        - reference_id: PMID:19262567
          supporting_text: "This protein associates with mRNAs containing the eIF4E-sensitivity
            element (4E-SE), and its overexpression alters the nuclear export of several
            eIF4E-sensitive mRNAs"
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:15161933
    review:
      summary: >-
        This annotation captures LRPPRC interaction with 14-3-3 proteins (specifically
        YWHAZ).
        The interaction was identified in a proteomic screen for 14-3-3 binding proteins.
      action: MODIFY
      reason: >-
        "Protein binding" is uninformative. The actual interaction is with 14-3-3
        proteins.
        Should be replaced with a more specific term if available, or kept but noted
        as
        non-core. The biological significance of this interaction is unclear.
      proposed_replacement_terms:
        - id: GO:0071889
          label: 14-3-3 protein binding
      supported_by:
        - reference_id: PMID:15161933
          supporting_text: "14-3-3-binding proteins were purified from extracts of
            interphase and mitotic HeLa cells"
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17050673
    review:
      summary: >-
        This annotation captures LRPPRC interaction with PPARGC1A (PGC-1alpha). This
        interaction is relevant to energy homeostasis and gluconeogenic gene regulation
        and is documented in the context of Leigh syndrome French Canadian variant.
      action: MODIFY
      reason: >-
        The interaction with PGC-1alpha is biologically significant but "protein binding"
        is uninformative. The specific interactor is a transcriptional coactivator.
      proposed_replacement_terms:
        - id: GO:0001223
          label: transcription coactivator binding
      supported_by:
        - reference_id: PMID:17050673
          supporting_text: Oct 18. Defects in energy homeostasis in Leigh 
            syndrome French Canadian variant through PGC-1alpha/LRP130 complex.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17314511
    review:
      summary: >-
        This annotation captures LRPPRC interaction with c-MYC (P01106), identified
        in
        a large-scale TAP/MudPIT study.
      action: KEEP_AS_NON_CORE
      reason: >-
        High-throughput interaction data; biological significance unclear. The term
        "protein binding" is uninformative but there is no more specific term available.
      supported_by:
        - reference_id: PMID:17314511
          supporting_text: Large-scale identification of c-MYC-associated 
            proteins using a combined TAP/MudPIT approach.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17353931
    review:
      summary: >-
        Large-scale protein-protein interaction mapping study. LRPPRC interactions
        with
        P01106 (MYC) and Q9Y2Q3 (GAB1) were identified.
      action: KEEP_AS_NON_CORE
      reason: >-
        High-throughput data with unclear biological significance for LRPPRC function.
      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:19262567
    review:
      summary: >-
        This annotation captures LRPPRC interaction with EIF4E. This is a functionally
        significant interaction related to nuclear mRNA export. LRPPRC binds simultaneously
        to EIF4E and 4ESE-containing mRNAs to promote mRNA export.
      action: MODIFY
      reason: >-
        This is a biologically meaningful interaction but "protein binding" is uninformative.
        EIF4E binding is relevant to the nuclear mRNA export function of LRPPRC.
      proposed_replacement_terms:
        - id: GO:0008190
          label: eukaryotic initiation factor 4E binding
      supported_by:
        - reference_id: PMID:19262567
          supporting_text: "we identified candidate cofactors of eIF4E mRNA export
            including LRPPRC"
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21150319
    review:
      summary: >-
        Proteomic profiling of Myc-associated proteins. LRPPRC interaction with MYC
        identified.
      action: KEEP_AS_NON_CORE
      reason: >-
        High-throughput data; biological significance for LRPPRC core function unclear.
      supported_by:
        - reference_id: PMID:21150319
          supporting_text: Dec 15. Proteomic profiling of Myc-associated 
            proteins.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:22045337
    review:
      summary: >-
        This annotation captures LRPPRC interaction with SLIRP (Q9GZT3). This is the
        most
        functionally significant protein interaction for LRPPRC - SLIRP and LRPPRC
        form
        a stable RNP complex essential for mitochondrial mRNA metabolism.
      action: MODIFY
      reason: >-
        The LRPPRC-SLIRP interaction is THE core functional interaction. "Protein
        binding"
        fails to capture its significance. These proteins are mutually stabilizing
        and
        function as an obligate complex.
      proposed_replacement_terms:
        - id: GO:0140693
          label: molecular condensate scaffold activity
      additional_reference_ids:
        - PMID:22661577
      supported_by:
        - reference_id: PMID:22661577
          supporting_text: "the LRPPRC/SLIRP complex suppresses mRNA degradation mediated
            by PNPase and SUV3 and promotes polyadenylation of mRNA"
        - reference_id: PMID:22045337
          supporting_text: LRPPRC is necessary for polyadenylation and 
            coordination of translation of mitochondrial mRNAs.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25959826
    review:
      summary: >-
        Interaction with APP (amyloid precursor protein) identified in neurodegenerative
        disease protein interaction study.
      action: KEEP_AS_NON_CORE
      reason: >-
        High-throughput interaction data; relevance to LRPPRC core function unclear.
      supported_by:
        - reference_id: PMID:25959826
          supporting_text: 2015 May 7. Quantitative interaction proteomics of 
            neurodegenerative disease proteins.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:26496610
    review:
      summary: >-
        Another study confirming LRPPRC-SLIRP interaction in a quantitative interactome
        study.
      action: ACCEPT
      reason: >-
        Confirms the core LRPPRC-SLIRP interaction, though "protein binding" remains
        uninformative.
      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:33961781
    review:
      summary: >-
        Dual proteome-scale network study confirming LRPPRC-SLIRP interaction.
      action: ACCEPT
      reason: >-
        Additional confirmation of core LRPPRC-SLIRP interaction.
      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:36931259
    review:
      summary: >-
        Study on 14-3-3 proteins; confirms LRPPRC interaction with 14-3-3 (YWHAZ).
      action: KEEP_AS_NON_CORE
      reason: >-
        14-3-3 binding is documented but biological significance for LRPPRC function
        unclear.
      supported_by:
        - reference_id: PMID:36931259
          supporting_text: A central chaperone-like role for 14-3-3 proteins in 
            human cells.
  - term:
      id: GO:0003697
      label: single-stranded DNA binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        This annotation is transferred from mouse ortholog. While UniProt states LRPPRC
        "Binds single-stranded DNA (By similarity)", this is not a well-established
        function for human LRPPRC. The primary binding function is to RNA.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        No direct experimental evidence for ssDNA binding by human LRPPRC. The protein's
        core function is RNA binding in mitochondria. DNA binding annotation should
        be
        deprioritized.
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        LRPPRC is present in cytoplasm, consistent with its mitochondrial localization
        and potential cytoskeletal interactions.
      action: ACCEPT
      reason: >-
        Cytoplasm is a broad term that encompasses mitochondria. This annotation is
        technically correct though less informative than the more specific mitochondrion
        annotation.
  - term:
      id: GO:1990904
      label: ribonucleoprotein complex
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        LRPPRC forms a stable RNP complex with SLIRP and mitochondrial mRNAs. This
        is central to its function.
      action: ACCEPT
      reason: >-
        The LRPPRC-SLIRP-mRNA complex is well-established and central to LRPPRC function.
      supported_by:
        - reference_id: PMID:22661577
          supporting_text: "which we find that cotranscriptionally binds to coding
            sequences of mRNAs"
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: >-
        IDA annotation based on immunofluorescence data (Human Protein Atlas). Confirms
        mitochondrial localization.
      action: ACCEPT
      reason: >-
        Core localization confirmed by immunofluorescence. Consistent with other evidence.
  - term:
      id: GO:0003729
      label: mRNA binding
    evidence_type: IDA
    original_reference_id: PMID:22661577
    review:
      summary: >-
        LRPPRC binds mitochondrial mRNAs as demonstrated by RNA immunoprecipitation
        and other biochemical approaches. This is a core molecular function.
      action: ACCEPT
      reason: >-
        mRNA binding is a well-established core function of LRPPRC, essential for
        its
        role in mRNA stabilization and delivery to the mitoribosome.
      supported_by:
        - reference_id: PMID:22661577
          supporting_text: "which we find that cotranscriptionally binds to coding
            sequences of mRNAs"
        - reference_id: PMID:12832482
          supporting_text: "they are directly bound to polyadenylated RNAs in vivo"
  - term:
      id: GO:0097222
      label: mitochondrial mRNA polyadenylation
    evidence_type: IDA
    original_reference_id: PMID:22661577
    review:
      summary: >-
        LRPPRC promotes polyadenylation of mitochondrial mRNAs via MTPAP. In vitro
        assays demonstrate LRPPRC enhances MTPAP-mediated polyadenylation.
      action: ACCEPT
      reason: >-
        This is a core function of LRPPRC. The study provides direct experimental
        evidence
        that LRPPRC promotes MTPAP-mediated polyadenylation of mt-mRNAs.
      supported_by:
        - reference_id: PMID:22661577
          supporting_text: "LRPPRC promoted the polyadenylation of mRNAs mediated
            by mitochondrial poly(A) polymerase (MTPAP) in vitro"
  - term:
      id: GO:1905638
      label: negative regulation of mitochondrial mRNA catabolic process
    evidence_type: IMP
    original_reference_id: PMID:22661577
    review:
      summary: >-
        LRPPRC/SLIRP complex suppresses 3'-5' exonucleolytic degradation of mt-mRNAs
        by PNPase and SUV3. Knockdown of LRPPRC/SLIRP leads to accelerated mRNA decay.
      action: ACCEPT
      reason: >-
        This is a core function of LRPPRC. The mutant phenotype (accelerated mRNA
        decay
        upon knockdown) provides direct evidence for this regulatory function.
      supported_by:
        - reference_id: PMID:22661577
          supporting_text: "the LRPPRC/SLIRP complex suppressed 3' exonucleolytic
            mRNA degradation mediated by PNPase and SUV3"
        - reference_id: PMID:22661577
          supporting_text: "Taken together with the accelerated decay of several mRNAs
            upon SLIRP knock down (Figure 2A), the results suggest that the LRPPRC/SLIRP
            complex stabilizes a set of mRNAs by suppressing 3′–5′ exonuclease activity
            performed by PNPase and SUV3"
  - term:
      id: GO:0005759
      label: mitochondrial matrix
    evidence_type: IDA
    original_reference_id: PMID:23275553
    review:
      summary: >-
        LRPPRC localizes to the mitochondrial matrix where it performs its mRNA
        metabolism functions. This is more specific than general mitochondrion annotation.
      action: ACCEPT
      reason: >-
        Mitochondrial matrix is the specific sub-compartment where LRPPRC functions
        in mRNA stabilization, polyadenylation, and delivery to the mitoribosome.
      supported_by:
        - reference_id: doi:10.1038/s41594-024-01365-9
          supporting_text: "LRPPRC-SLIRP operate in the mitochondrial matrix, engaging
            mt-mRNAs and the mitoribosome"
        - reference_id: PMID:23275553
          supporting_text: 2012 Dec 28. Alternative translation initiation 
            augments the human mitochondrial proteome.
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: HTP
    original_reference_id: PMID:34800366
    review:
      summary: >-
        High-throughput quantitative mitochondrial proteome study confirms LRPPRC
        as a mitochondrial protein.
      action: ACCEPT
      reason: >-
        Additional confirmation of core localization from high-quality proteomics
        study.
      supported_by:
        - reference_id: PMID:34800366
          supporting_text: Epub 2021 Nov 19. Quantitative high-confidence human 
            mitochondrial proteome and its dynamics in cellular context.
  - term:
      id: GO:0031625
      label: ubiquitin protein ligase binding
    evidence_type: IPI
    original_reference_id: PMID:19725078
    review:
      summary: >-
        LRPPRC interacts with Parkin (O60260), an E3 ubiquitin ligase. Study examined
        Parkin interactors in context of mitochondrial function.
      action: KEEP_AS_NON_CORE
      reason: >-
        The interaction with Parkin is documented but its biological significance
        for
        LRPPRC function is unclear. May relate to mitochondrial quality control but
        is not a core LRPPRC function.
      supported_by:
        - reference_id: PMID:19725078
          supporting_text: Proteomic analysis of increased Parkin expression and
            its interactants provides evidence for a role in modulation of 
            mitochondrial function.
  - term:
      id: GO:0016020
      label: membrane
    evidence_type: HDA
    original_reference_id: PMID:19946888
    review:
      summary: >-
        Membrane proteome study of NK cells identified LRPPRC. The annotation is
        very general and less informative than more specific localizations.
      action: KEEP_AS_NON_CORE
      reason: >-
        This is a very general annotation. LRPPRC is primarily a soluble matrix
        protein, though it may associate with membranes in some contexts.
      supported_by:
        - reference_id: PMID:19946888
          supporting_text: Defining the membrane proteome of NK cells.
  - term:
      id: GO:0005759
      label: mitochondrial matrix
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9837034
    review:
      summary: >-
        Reactome pathway "SLIRP:LRPPRC binds mitochondrial RNAs" places the complex
        in the mitochondrial matrix.
      action: ACCEPT
      reason: >-
        Consistent with other evidence for mitochondrial matrix localization.
  - term:
      id: GO:0003723
      label: RNA binding
    evidence_type: HDA
    original_reference_id: PMID:22658674
    review:
      summary: >-
        Atlas of mammalian mRNA-binding proteins identifies LRPPRC as an RNA-binding
        protein through oligo(dT) capture and mass spectrometry.
      action: ACCEPT
      reason: >-
        RNA binding is a core function of LRPPRC, confirmed by this systematic study.
      supported_by:
        - reference_id: PMID:22658674
          supporting_text: May 31. Insights into RNA biology from an atlas of 
            mammalian mRNA-binding proteins.
  - term:
      id: GO:0003723
      label: RNA binding
    evidence_type: HDA
    original_reference_id: PMID:22681889
    review:
      summary: >-
        mRNA-bound proteome study confirms LRPPRC as an RNA-binding protein.
      action: ACCEPT
      reason: >-
        Additional confirmation of core RNA-binding function.
      supported_by:
        - reference_id: PMID:22681889
          supporting_text: The mRNA-bound proteome and its global occupancy 
            profile on protein-coding transcripts.
  - term:
      id: GO:0005874
      label: microtubule
    evidence_type: IDA
    original_reference_id: PMID:21525035
    review:
      summary: >-
        Study on peroxisome motility found LRPPRC associated with microtubules.
        This relates to proposed cytoskeletal interactions.
      action: KEEP_AS_NON_CORE
      reason: >-
        Microtubule association has been reported but is not the primary localization
        or function of LRPPRC. May be related to mitochondrial transport along
        microtubules but is not a core function.
      supported_by:
        - reference_id: PMID:21525035
          supporting_text: Apr 26. PEX14 is required for microtubule-based 
            peroxisome motility in human cells.
  - term:
      id: GO:0042645
      label: mitochondrial nucleoid
    evidence_type: IDA
    original_reference_id: PMID:18063578
    review:
      summary: >-
        LRPPRC was identified in the mitochondrial nucleoid, the structure containing
        mtDNA and associated proteins. This localization is consistent with roles
        in mitochondrial gene expression.
      action: KEEP_AS_NON_CORE
      reason: >-
        Nucleoid localization is documented but LRPPRC's primary function is in
        mRNA metabolism rather than DNA-related processes. Nucleoid association
        may reflect physical proximity rather than functional involvement.
      supported_by:
        - reference_id: PMID:18063578
          supporting_text: 2007 Dec 6. The layered structure of human 
            mitochondrial DNA nucleoids.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:12762840
    review:
      summary: >-
        Nuclear localization demonstrated by immunofluorescence and GFP-tagging
        in cultured cells.
      action: KEEP_AS_NON_CORE
      reason: >-
        Nuclear localization is documented but represents a minor fraction of
        total cellular LRPPRC. The majority is mitochondrial.
      supported_by:
        - reference_id: PMID:12762840
          supporting_text: "LRPPRC appears in both cytosol and nuclei of cultured
            cells"
  - term:
      id: GO:0048487
      label: beta-tubulin binding
    evidence_type: IDA
    original_reference_id: PMID:12762840
    review:
      summary: >-
        Study reported LRPPRC colocalization with beta-tubulin and suggested
        direct interaction. However, this is not the primary function.
      action: KEEP_AS_NON_CORE
      reason: >-
        Beta-tubulin binding/colocalization was reported in early studies but is
        not the core function of LRPPRC. The primary function is mitochondrial
        mRNA metabolism. Cytoskeletal interactions may be related to mitochondrial
        transport but are secondary.
      supported_by:
        - reference_id: PMID:12762840
          supporting_text: "colocalizes with mitochondria and beta-tubulin rather
            than with alpha-actin in the cytosol"
  - term:
      id: GO:0051015
      label: actin filament binding
    evidence_type: IDA
    original_reference_id: PMID:12762840
    negated: true
    review:
      summary: >-
        The study explicitly showed LRPPRC does NOT colocalize with actin filaments.
        This is a negated annotation (NOT actin filament binding).
      action: ACCEPT
      reason: >-
        Negated annotations are valuable. The study specifically tested and excluded
        actin filament binding/colocalization.
      supported_by:
        - reference_id: PMID:12762840
          supporting_text: "colocalizes with mitochondria and beta-tubulin rather
            than with alpha-actin"
  - term:
      id: GO:0000794
      label: condensed nuclear chromosome
    evidence_type: IDA
    original_reference_id: PMID:12762840
    review:
      summary: >-
        Study showed LRPPRC association with condensed chromosomes during mitosis.
        GFP-tagged CECR2B colocalized with condensed DNA. LRPPRC showed
        phase-dependent organization around separating chromosomes.
      action: KEEP_AS_NON_CORE
      reason: >-
        This observation relates to potential nuclear functions during mitosis
        but is not a core LRPPRC function. The primary function is mitochondrial.
      supported_by:
        - reference_id: PMID:12762840
          supporting_text: "exhibits phase-dependent organization around separating
            chromosomes in mitotic cells"
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: IDA
    original_reference_id: PMID:12762840
    review:
      summary: >-
        Early study demonstrating mitochondrial colocalization of LRPPRC.
      action: ACCEPT
      reason: >-
        Core localization confirmed by multiple approaches.
      supported_by:
        - reference_id: PMID:12762840
          supporting_text: "colocalizes with mitochondria and beta-tubulin"
  - term:
      id: GO:0005856
      label: cytoskeleton
    evidence_type: IDA
    original_reference_id: PMID:12762840
    review:
      summary: >-
        LRPPRC was reported to colocalize with cytoskeletal elements, specifically
        beta-tubulin but not actin.
      action: KEEP_AS_NON_CORE
      reason: >-
        Cytoskeletal association is documented but is not the primary localization
        or function. May relate to mitochondrial transport but is secondary to
        the matrix-localized mRNA metabolism function.
      supported_by:
        - reference_id: PMID:12762840
          supporting_text: Novel complex integrating mitochondria and the 
            microtubular cytoskeleton with chromosome remodeling and tumor 
            suppressor RASSF1 deduced by in silico homology analysis, 
            interaction cloning in yeast, and colocalization in cultured cells.
  - term:
      id: GO:0008017
      label: microtubule binding
    evidence_type: TAS
    original_reference_id: PMID:12762840
    review:
      summary: >-
        TAS annotation based on colocalization studies showing LRPPRC association
        with microtubules/beta-tubulin.
      action: KEEP_AS_NON_CORE
      reason: >-
        Microtubule binding/association is documented but is not the core molecular
        function. The primary function is RNA binding in mitochondrial mRNA metabolism.
      supported_by:
        - reference_id: PMID:12762840
          supporting_text: Novel complex integrating mitochondria and the 
            microtubular cytoskeleton with chromosome remodeling and tumor 
            suppressor RASSF1 deduced by in silico homology analysis, 
            interaction cloning in yeast, and colocalization in cultured cells.
  - term:
      id: GO:0047497
      label: mitochondrion transport along microtubule
    evidence_type: TAS
    original_reference_id: PMID:12762840
    review:
      summary: >-
        Annotation suggests LRPPRC involvement in mitochondrial transport along
        microtubules, based on proposed complex linking mitochondria to cytoskeleton.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        While the study proposed a role in linking mitochondria to microtubules,
        subsequent work has not validated this as a primary function. The well-
        established functions are in mitochondrial mRNA metabolism. This annotation
        may over-represent an unconfirmed hypothesis.
      supported_by:
        - reference_id: PMID:12762840
          supporting_text: Novel complex integrating mitochondria and the 
            microtubular cytoskeleton with chromosome remodeling and tumor 
            suppressor RASSF1 deduced by in silico homology analysis, 
            interaction cloning in yeast, and colocalization in cultured cells.
  - term:
      id: GO:0048471
      label: perinuclear region of cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:12762840
    review:
      summary: >-
        LRPPRC was observed in the perinuclear region, consistent with mitochondrial
        localization as mitochondria often cluster in this region.
      action: KEEP_AS_NON_CORE
      reason: >-
        Perinuclear localization is consistent with mitochondrial distribution but
        is less informative than the specific mitochondrial matrix annotation.
      supported_by:
        - reference_id: PMID:12762840
          supporting_text: Novel complex integrating mitochondria and the 
            microtubular cytoskeleton with chromosome remodeling and tumor 
            suppressor RASSF1 deduced by in silico homology analysis, 
            interaction cloning in yeast, and colocalization in cultured cells.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:15907802
    review:
      summary: >-
        Study on MAP1S (C19ORF5) identified its interaction with LRPPRC. MAP1S
        was proposed as part of a complex linking mitochondria to cytoskeleton.
      action: KEEP_AS_NON_CORE
      reason: >-
        Interaction is documented but biological significance for LRPPRC core
        function is unclear.
      supported_by:
        - reference_id: PMID:15907802
          supporting_text: Putative tumor suppressor RASSF1 interactive protein 
            and cell death inducer C19ORF5 is a DNA binding protein.
  - term:
      id: GO:0003723
      label: RNA binding
    evidence_type: NAS
    original_reference_id: PMID:12832482
    review:
      summary: >-
        Non-traceable author statement supporting RNA binding function based on
        the landmark Mili & Pinol-Roma 2003 study.
      action: ACCEPT
      reason: >-
        RNA binding is a core function, extensively validated by this and other studies.
      supported_by:
        - reference_id: PMID:12832482
          supporting_text: "LRP130 is a novel type of RNA-binding protein that associates
            with both nuclear and mitochondrial mRNAs"
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:12832482
    review:
      summary: >-
        IDA evidence for nuclear localization from the 2003 study that characterized
        LRPPRC as binding both nuclear and mitochondrial RNAs.
      action: KEEP_AS_NON_CORE
      reason: >-
        Nuclear localization is documented for a fraction of LRPPRC. The study showed
        most LRPPRC is mitochondrial but some is nuclear.
      supported_by:
        - reference_id: PMID:12832482
          supporting_text: "only a fraction of LRP130 proteins are in nuclei"
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: IDA
    original_reference_id: PMID:12832482
    review:
      summary: >-
        Key study demonstrating predominant mitochondrial localization of LRPPRC.
      action: ACCEPT
      reason: >-
        This is the core localization for LRPPRC function.
      supported_by:
        - reference_id: PMID:12832482
          supporting_text: "The majority of LRP130 proteins are located within mitochondria,
            where they are directly bound to polyadenylated RNAs in vivo"
references:
  - 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:0000107
    title: Automatic transfer of experimentally verified manual GO annotation 
      data to orthologs using Ensembl Compara
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: PMID:12762840
    title: Novel complex integrating mitochondria and the microtubular 
      cytoskeleton with chromosome remodeling and tumor suppressor RASSF1 
      deduced by in silico homology analysis, interaction cloning in yeast, and 
      colocalization in cultured cells.
    findings:
      - statement: LRPPRC colocalizes with mitochondria and beta-tubulin but not
          actin
      - statement: Phase-dependent organization around separating chromosomes in
          mitotic cells
  - id: PMID:12832482
    title: LRP130, a pentatricopeptide motif protein with a noncanonical 
      RNA-binding domain, is bound in vivo to mitochondrial and nuclear RNAs.
    findings:
      - statement: Majority of LRPPRC is mitochondrial, directly bound to 
          poly(A) RNAs in vivo
      - statement: A fraction is nuclear, bound to some of same RNAs as hnRNP A1
      - statement: RNA binding maps to C-terminal domain containing only 2 of 11
          PPR motifs
  - id: PMID:15161933
    title: Comprehensive proteomic analysis of interphase and mitotic 
      14-3-3-binding proteins.
    findings:
      - statement: LRPPRC identified as 14-3-3 binding protein
  - id: PMID:15907802
    title: Putative tumor suppressor RASSF1 interactive protein and cell death 
      inducer C19ORF5 is a DNA binding protein.
    findings: []
  - id: PMID:17050673
    title: Defects in energy homeostasis in Leigh syndrome French Canadian 
      variant through PGC-1alpha/LRP130 complex.
    findings:
      - statement: LRPPRC interacts with PGC-1alpha to regulate gluconeogenic 
          genes
  - id: PMID:17314511
    title: Large-scale identification of c-MYC-associated proteins using a 
      combined TAP/MudPIT approach.
    findings: []
  - id: PMID:17353931
    title: Large-scale mapping of human protein-protein interactions by mass 
      spectrometry.
    findings: []
  - id: PMID:18063578
    title: The layered structure of human mitochondrial DNA nucleoids.
    findings:
      - statement: LRPPRC identified in mitochondrial nucleoid
  - id: PMID:19262567
    title: Molecular dissection of the eukaryotic initiation factor 4E (eIF4E) 
      export-competent RNP.
    findings:
      - statement: LRPPRC binds EIF4E and promotes nuclear mRNA export
  - id: PMID:19725078
    title: Proteomic analysis of increased Parkin expression and its 
      interactants provides evidence for a role in modulation of mitochondrial 
      function.
    findings:
      - statement: LRPPRC interacts with Parkin
  - id: PMID:19946888
    title: Defining the membrane proteome of NK cells.
    findings: []
  - id: PMID:21150319
    title: Proteomic profiling of Myc-associated proteins.
    findings: []
  - id: PMID:21525035
    title: PEX14 is required for microtubule-based peroxisome motility in human 
      cells.
    findings: []
  - id: PMID:22045337
    title: LRPPRC is necessary for polyadenylation and coordination of 
      translation of mitochondrial mRNAs.
    findings: []
  - id: PMID:22658674
    title: Insights into RNA biology from an atlas of mammalian mRNA-binding 
      proteins.
    findings:
      - statement: LRPPRC identified as mRNA-binding protein in systematic study
  - id: PMID:22661577
    title: LRPPRC/SLIRP suppresses PNPase-mediated mRNA decay and promotes 
      polyadenylation in human mitochondria.
    findings:
      - statement: LRPPRC/SLIRP suppresses 3'-5' mRNA degradation by PNPase/SUV3
      - statement: LRPPRC promotes MTPAP-mediated polyadenylation
      - statement: Copy numbers of mt-mRNAs range from 6000 to 51000 per cell
      - statement: Half-lives of mt-mRNAs range from 68-231 minutes
  - id: PMID:22681889
    title: The mRNA-bound proteome and its global occupancy profile on 
      protein-coding transcripts.
    findings: []
  - id: PMID:23275553
    title: Alternative translation initiation augments the human mitochondrial 
      proteome.
    findings:
      - statement: LRPPRC localized to mitochondrial matrix
  - id: PMID:25959826
    title: Quantitative interaction proteomics of neurodegenerative disease 
      proteins.
    findings: []
  - id: PMID:26496610
    title: A human interactome in three quantitative dimensions organized by 
      stoichiometries and abundances.
    findings: []
  - id: PMID:33961781
    title: Dual proteome-scale networks reveal cell-specific remodeling of the 
      human interactome.
    findings: []
  - id: PMID:34800366
    title: Quantitative high-confidence human mitochondrial proteome and its 
      dynamics in cellular context.
    findings:
      - statement: High-throughput confirmation of LRPPRC as mitochondrial 
          protein
  - id: PMID:36931259
    title: A central chaperone-like role for 14-3-3 proteins in human cells.
    findings: []
  - id: Reactome:R-HSA-9837034
    title: SLIRP:LRPPRC binds mitochondrial RNAs
    findings: []
  - id: file:human/LRPPRC/LRPPRC-deep-research-falcon.md
    title: Deep research summary for LRPPRC including 2024 structural and 
      functional studies
    findings:
      - statement: Cryo-EM structure of LRPPRC-SLIRP on mitoribosome (Singh et 
          al. 2024)
      - statement: LRPPRC contacts mS39 and mS31 for mRNA delivery
      - statement: SLIRP directly holds mRNA in corridor
      - statement: Transcript-specific translation efficiency changes upon 
          LRPPRC loss
      - statement: LRPPRC acts as mRNA holdase maintaining proper folding (Moran
          et al. 2024)
      - statement: LRPPRC-SLIRP required throughout mt-mRNA life cycle 
          (Rubalcava-Gracia et al. 2024)
core_functions:
  - description: >-
      Mitochondrial mRNA stabilization via suppression of PNPase/SUV3-mediated 3'-5'
      decay.
      LRPPRC-SLIRP complex binds mt-mRNAs and protects them from degradation.
    molecular_function:
      id: GO:0003729
      label: mRNA binding
    directly_involved_in:
      - id: GO:1905638
        label: negative regulation of mitochondrial mRNA catabolic process
    locations:
      - id: GO:0005759
        label: mitochondrial matrix
  - description: >-
      Promotion of mitochondrial mRNA polyadenylation via MTPAP. LRPPRC enhances
      MTPAP-mediated addition of poly(A) tails to mt-mRNAs.
    molecular_function:
      id: GO:0003729
      label: mRNA binding
    directly_involved_in:
      - id: GO:0097222
        label: mitochondrial mRNA polyadenylation
    locations:
      - id: GO:0005759
        label: mitochondrial matrix
  - description: >-
      mRNA delivery to the mitoribosome. LRPPRC docks on small subunit via mS39/mS31,
      forming a corridor with SLIRP for mRNA handoff to the decoding center.
    molecular_function:
      id: GO:0003729
      label: mRNA binding
    directly_involved_in:
      - id: GO:0070129
        label: regulation of mitochondrial translation
    locations:
      - id: GO:0005759
        label: mitochondrial matrix
  - description: >-
      mRNA holdase activity maintaining proper mt-mRNA folding for efficient translation.
    molecular_function:
      id: GO:0003729
      label: mRNA binding
    directly_involved_in:
      - id: GO:0070129
        label: regulation of mitochondrial translation
    locations:
      - id: GO:0005759
        label: mitochondrial matrix
proposed_new_terms: []
suggested_questions:
  - question: Is the nuclear mRNA export function of LRPPRC biologically 
      significant or a minor moonlighting activity?
  - question: What is the molecular basis for transcript-specific effects on 
      translation efficiency?
  - question: How does LRPPRC recognize its mRNA substrates without 
      sequence-specific binding motifs?
suggested_experiments:
  - description: CLIP-seq to map LRPPRC binding sites on mt-mRNAs at nucleotide 
      resolution
  - description: Structure-function analysis of LRPPRC-mS39/mS31 interaction 
      interface
  - description: Time-resolved analysis of mRNA delivery from LRPPRC-SLIRP to 
      active ribosomes