Affinage

RPP38

Ribonuclease P protein subunit p38 · UniProt P78345

Length
283 aa
Mass
31.8 kDa
Annotated
2026-04-28
32 papers in source corpus 15 papers cited in narrative 15 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RPP38 is a protein subunit shared by the human RNase P and RNase MRP ribonucleoprotein complexes, where it functions in tRNA precursor processing and ribosomal RNA maturation. RPP38 directly binds the H1 RNA component of RNase P through an L7Ae-family kink-turn (K-turn) recognition mechanism, as defined by crystal structures of the archaeal homolog PhoRpp38, and engages in protein–protein interactions with multiple other complex subunits including hPop1, Rpp21, Rpp29, Rpp30, and Rpp40 (PMID:9037013, PMID:11455963, PMID:27114305, PMID:15096576). Normal RPP38 expression is required for intact RNase P activity and tRNA processing; both overexpression and depletion cause accumulation of tRNA precursors, and RPP38 knockdown coordinately destabilizes a subset of other RNase P subunits (PMID:12907726, PMID:12552092). RPP38 localizes to the nucleolus via a basic domain that directs nucleolar targeting independently of its association with either RNase P or RNase MRP (PMID:10444065, PMID:11694598).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1997 High

    Identification of RPP38 as an RNase P protein subunit established that human nuclear RNase P contains a previously uncharacterized ~38 kDa polypeptide that copurifies with enzymatic activity and binds H1 RNA.

    Evidence Copurification from HeLa cell extracts, immunodepletion, cDNA cloning, in vitro RNA binding

    PMID:9037013

    Open questions at the time
    • Binding site on H1 RNA not mapped
    • Functional requirement for catalysis not yet tested
  2. 1998 High

    Confirmation that RPP38 is a bona fide component of catalytically active RNase P resolved whether the copurifying protein was a contaminant versus a true subunit.

    Evidence Immunoprecipitation of active holoenzyme with anti-Rpp38 polyclonal antibodies; recognition by Th autoimmune sera

    PMID:9630247

    Open questions at the time
    • Whether RPP38 is shared with RNase MRP not yet known
    • Stoichiometry within the complex undefined
  3. 1999 High

    Demonstration that RPP38 is a shared subunit of both RNase P and RNase MRP, and localizes to the nucleolus and Cajal bodies, placed it at the intersection of tRNA and rRNA processing pathways.

    Evidence UV crosslinking and co-IP with anti-Rpp38 antibodies; VSV-tagged Rpp38 co-precipitates both complexes; fluorescence microscopy with domain deletions

    PMID:10199568 PMID:10444065

    Open questions at the time
    • Domain responsible for nucleolar targeting not yet defined
    • Mechanism of dual complex association unclear
  4. 2001 High

    Mapping of RPP38's direct RNA and protein contacts within the RNase P holoenzyme — binding H1 RNA and interacting with hPop1, Rpp21, Rpp29, Rpp30, and Rpp40 — defined its position within the complex architecture and showed that nucleolar localization is mediated by a basic domain independent of complex association.

    Evidence Yeast three-hybrid and UV crosslinking for RNA contacts; yeast two-hybrid for protein contacts; deletion/reporter analysis for nucleolar targeting

    PMID:11158571 PMID:11455963 PMID:11694598

    Open questions at the time
    • Three-dimensional binding mode unknown
    • Protein–protein interactions from yeast two-hybrid not validated by pull-down
    • Whether basic domain contributes to RNA binding untested
  5. 2002 High

    Resolution of the Th40/Rpp38 identity question and demonstration that RPP38 does not directly contact the P3 domain of MRP RNA clarified which subunits mediate RNA recognition in RNase MRP versus RNase P.

    Evidence Reconstitution, UV crosslinking, immunoprecipitation with patient antisera and recombinant proteins

    PMID:12483731

    Open questions at the time
    • Which RNA element RPP38 contacts in MRP RNA not identified
    • Functional consequences of RPP38 absence from P3 binding not tested
  6. 2003 High

    Gain- and loss-of-function experiments established that RPP38 is functionally required for RNase P activity and tRNA precursor processing in vivo, and that its expression coordinately stabilizes a subset of other RNase P subunits.

    Evidence Stable overexpression, siRNA and EGS knockdown in HeLa cells with in vitro RNase P activity and tRNA precursor accumulation assays

    PMID:12552092 PMID:12907726

    Open questions at the time
    • Which subunits are directly stabilized by RPP38 versus indirectly affected not distinguished
    • Whether tRNA processing defects are solely RNase P–dependent not tested
  7. 2004 High

    Systematic in vitro reconstitution mapping of all pairwise protein–protein and protein–RNA contacts within human RNase MRP/RNase P placed RPP38 within a comprehensive interaction network and refined the ribonucleoprotein architecture model.

    Evidence GST pull-down with recombinant subunits and mutant RNA analysis

    PMID:15096576

    Open questions at the time
    • Architecture not validated by high-resolution structural method for the human complex
    • Functional hierarchy of interactions unknown
  8. 2006 High

    Sedimentation analysis demonstrated that RPP38 is associated with all RNase MRP particles (both 12S and 60–80S forms), distinguishing it from subunits that partition into only one complex subpopulation.

    Evidence Glycerol gradient sedimentation and co-IP with VSV-tagged subunits

    PMID:16723659

    Open questions at the time
    • Functional significance of association with higher-order (60–80S) particles not defined
    • Whether RPP38 bridges subcomplexes unknown
  9. 2016 High

    Crystal structures of the archaeal homolog PhoRpp38 bound to K-turn RNA motifs revealed the molecular basis of RPP38's RNA recognition: an L7Ae-family fold that contacts G·A pairs and a nucleotide bulge via specific residues, with one protein copy binding K-turns in two stem-loops of RNase P RNA.

    Evidence X-ray crystallography (3.4 Å then improved to 2.1 Å and 3.1 Å), structure-based mutagenesis, pull-down assays

    PMID:27114305 PMID:29372908

    Open questions at the time
    • Human RPP38–RNA complex structure not yet determined
    • Whether K-turn recognition mode is identical in the human enzyme untested
  10. 2017 Medium

    Live-cell imaging at laser-induced DNA damage sites showed that RPP38 is not recruited to double-strand breaks, distinguishing it from Rpp29 and Rpp21 and delimiting its functional repertoire to RNA processing.

    Evidence Laser microirradiation, live-cell fluorescence imaging, siRNA depletion

    PMID:28432356

    Open questions at the time
    • Negative result from a single study; other non-canonical roles not excluded
    • Whether RPP38 participates in other stress responses untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • A high-resolution structure of human RPP38 within the intact human RNase P or RNase MRP holoenzyme, and a mechanistic understanding of how RPP38 coordinates subunit stability with catalytic function, remain unresolved.
  • No cryo-EM or crystal structure of the human holoenzyme with RPP38 resolved
  • Mechanism by which RPP38 stabilizes other subunits is unknown
  • Potential non-canonical functions beyond tRNA/rRNA processing unexplored

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 4 GO:0005198 structural molecule activity 3
Localization
GO:0005634 nucleus 2 GO:0005730 nucleolus 2
Pathway
R-HSA-8953854 Metabolism of RNA 4
Partners
POP1RPP20RPP21RPP25RPP29RPP30RPP40
Complex memberships
RNase MRPRNase P

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 RPP38 (p38) was identified as a protein subunit of human RNase P that copurifies with the enzyme activity from HeLa cells, and was shown to bind to H1 RNA (the RNA component of RNase P) in vitro. Protein copurification, immunodepletion with autoimmune sera, immunoblotting, cDNA cloning from peptide fragments, in vitro RNA binding Proceedings of the National Academy of Sciences of the United States of America High 9037013
1998 Recombinant Rpp38 is recognized by Th autoimmune sera from systemic sclerosis patients, and polyclonal antibodies against recombinant Rpp38 precipitate active RNase P holoenzyme, confirming Rpp38 as a bona fide subunit of catalytically active RNase P. Recombinant protein immunoblotting, immunoprecipitation of active holoenzyme with polyclonal antibodies RNA (New York, N.Y.) High 9630247
1999 Rpp38 is uniformly distributed in the nucleolus and possesses a functional domain required for subnucleolar localization that can direct a reporter protein to nucleoli. Rpp38 also resides in coiled bodies. Fluorescence microscopy with reporter fusions, domain deletion analysis in tissue culture cells The Journal of cell biology High 10444065
1999 Rpp38 is associated with the RNase MRP complex in addition to RNase P, demonstrated by UV crosslinking and immunoprecipitation with anti-Rpp38 antibodies, and by co-precipitation of both RNase P and RNase MRP complexes when VSV-tagged Rpp38 is expressed in HeLa cells. UV crosslinking followed by immunoprecipitation, VSV-tagged protein expression with co-immunoprecipitation RNA (New York, N.Y.) High 10199568
2001 Rpp38 participates in protein-protein interactions with other subunits of human nuclear RNase P (hpop1, Rpp21, Rpp29, Rpp30, and Rpp40), as determined by yeast two-hybrid analysis. Yeast two-hybrid system Proceedings of the National Academy of Sciences of the United States of America Medium 11158571
2001 Rpp38 directly interacts with H1 RNA (the RNA subunit of human nuclear RNase P), as shown by yeast three-hybrid analysis and confirmed by direct UV crosslinking studies of purified RNase P holoenzyme. Yeast three-hybrid system, UV crosslinking of purified holoenzyme RNA (New York, N.Y.) High 11455963
2001 The nucleolar accumulation of Rpp38 is mediated by a basic domain that directs nucleolar targeting independently of its association with the RNase MRP and RNase P complexes. A deletion mutant of Rpp38 was identified that preferentially associates with the RNase MRP complex, providing a clue about differences in protein composition between RNase MRP and RNase P. Mutant/deletion analysis with fluorescence microscopy in cell culture, co-immunoprecipitation with complex-specific antibodies Molecular biology of the cell High 11694598
2002 The previously defined Th40 autoantigen was shown to be identical to Rpp38 by reconstitution experiments and UV crosslinking. However, Rpp38 did not directly bind the P3 domain of RNase MRP RNA; instead, Rpp20 and Rpp25 interact with the P3 domain. Reconstitution experiments, UV crosslinking, immunoprecipitation with patient antisera and recombinant proteins Arthritis and rheumatism High 12483731
2003 Constitutive overexpression of exogenous tagged Rpp38 in HeLa cells impairs RNase P activity in vitro and causes accumulation of tRNA precursors; siRNA-mediated inhibition of Rpp38 also causes accumulation of the initiator methionine tRNA precursor. These results demonstrate that normal expression of Rpp38 is required for biosynthesis of intact RNase P and for normal tRNA processing. Stable transfection of tagged Rpp38, siRNA knockdown, in vitro RNase P activity assay, tRNA precursor analysis Nucleic acids research High 12907726
2003 EGS-mediated inhibition of Rpp38 expression in HeLa cells leads to coordinate down-regulation of four other RNase P protein subunits (but not all), demonstrating that Rpp38 expression is connected to the stable expression of a subset of other RNase P subunits. External guide sequence (EGS) technology, RT-PCR and immunoblotting of multiple subunits Proceedings of the National Academy of Sciences of the United States of America Medium 12552092
2004 GST pull-down experiments defined direct protein-protein interactions among human RNase MRP/RNase P subunits, including Rpp38. Six direct protein-RNA interactions were also identified, and distinct regions of MRP RNA are involved in direct interaction with protein subunits, providing a model for ribonucleoprotein architecture. GST pull-down, mutant RNA analysis, reconstitution Nucleic acids research High 15096576
2006 Glycerol gradient sedimentation and co-immunoprecipitation showed that Rpp38 (along with hPop1, Rpp40, and Rpp30) sediments in both 12S and 60-80S fractions, and is associated with all RNase MRP complexes, distinguishing it from subunits that associate only with RNase P or only a subset of RNase MRP particles. Glycerol gradient sedimentation, co-immunoprecipitation with VSV-epitope-tagged subunits RNA (New York, N.Y.) High 16723659
2016 The crystal structure of archaeal PhoRpp38 (homologue of human Rpp38) in complex with an RNA K-turn motif revealed that Lys35, Asn38, Glu39, and Lys42 interact with characteristic G·A and A·G pairs, and Ile93, Glu94, and Val95 interact with the nucleotide bulge. Structure-based mutagenesis showed that residues for SL12 binding also mediate SL16 binding, indicating each PhoRpp38 binds K-turns in two stem-loops of RNase P RNA. X-ray crystallography (3.4 Å), structure-based mutagenesis, pull-down assay Biochemical and biophysical research communications High 27114305
2018 Improved crystal structures of archaeal PhoRpp38 (homologue of human Rpp38) in complex with K-turn motifs P12.1 and P12.2 at 2.1 Å and 3.1 Å resolution identified additional interacting residues (Thr37, Asp59, Lys84, Glu94, Ala96, Ala98) contacting the three-nucleotide bulge, further defining the structural basis for K-turn recognition. X-ray crystallography (2.1 Å and 3.1 Å), affinity purification of multi-protein RNA complexes Acta crystallographica. Section F, Structural biology communications High 29372908
2017 Rpp38 (along with Rpp14 and Rpp25) was NOT recruited to laser-microirradiated DNA damage sites, in contrast to Rpp29 and Rpp21, indicating that Rpp38 does not participate in homology-directed repair of double-strand breaks. Laser microirradiation, live-cell fluorescence imaging, loss-of-function (siRNA depletion) Scientific reports Medium 28432356

Source papers

Stage 0 corpus · 32 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Characterization of two scleroderma autoimmune antigens that copurify with human ribonuclease P. Proceedings of the National Academy of Sciences of the United States of America 97 9037013
2004 Mutual interactions between subunits of the human RNase MRP ribonucleoprotein complex. Nucleic acids research 84 15096576
1999 Localization in the nucleolus and coiled bodies of protein subunits of the ribonucleoprotein ribonuclease P. The Journal of cell biology 77 10444065
2006 Inventory and analysis of the protein subunits of the ribonucleases P and MRP provides further evidence of homology between the yeast and human enzymes. Nucleic acids research 59 16998185
1999 RNA-protein interactions in the human RNase MRP ribonucleoprotein complex. RNA (New York, N.Y.) 59 10199568
1998 Autoantigenic properties of some protein subunits of catalytically active complexes of human ribonuclease P. RNA (New York, N.Y.) 52 9630247
2001 Protein-protein interactions with subunits of human nuclear RNase P. Proceedings of the National Academy of Sciences of the United States of America 51 11158571
2002 Identity of the RNase MRP- and RNase P-associated Th/To autoantigen. Arthritis and rheumatism 50 12483731
2000 Architecture and function of the human endonucleases RNase P and RNase MRP. IUBMB life 50 10995027
2001 Protein-RNA interactions in the subunits of human nuclear RNase P. RNA (New York, N.Y.) 48 11455963
1999 Rpp14 and Rpp29, two protein subunits of human ribonuclease P. RNA (New York, N.Y.) 48 10024167
2002 Purification and characterization of Rpp25, an RNA-binding protein subunit of human ribonuclease P. RNA (New York, N.Y.) 47 12003489
2002 Differences in autoantibody response to Th/To between systemic sclerosis and other autoimmune diseases. Annals of the rheumatic diseases 46 12176814
2006 Differential association of protein subunits with the human RNase MRP and RNase P complexes. RNA (New York, N.Y.) 44 16723659
2014 Autoantibodies to the mitochondrial RNA processing (MRP) complex also known as Th/To autoantigen. Autoimmunity reviews 29 25462581
2017 A role of human RNase P subunits, Rpp29 and Rpp21, in homology directed-repair of double-strand breaks. Scientific reports 25 28432356
2020 Pilot study of combined aerobic and resistance exercise on fatigue for patients with head and neck cancer: Inflammatory and epigenetic changes. Brain, behavior, and immunity 22 32330594
1999 Construction and characterization of a H19 epitope point mutant of MDV CVI988/Rispens strain. Acta virologica 19 10696440
2001 Basic domains target protein subunits of the RNase MRP complex to the nucleolus independently of complex association. Molecular biology of the cell 18 11694598
2004 Inhibition of the expression of the human RNase P protein subunits Rpp21, Rpp25, Rpp29 by external guide sequences (EGSs) and siRNA. Journal of molecular biology 16 15351636
2016 Structural basis for recognition of a kink-turn motif by an archaeal homologue of human RNase P protein Rpp38. Biochemical and biophysical research communications 13 27114305
2003 Coordinate inhibition of expression of several genes for protein subunits of human nuclear RNase P. Proceedings of the National Academy of Sciences of the United States of America 13 12552092
2004 Analyzing the H19- and T65-epitopes in 38 kd phosphorylated protein of Marek's disease viruses and comparing chicken immunological reactions to viruses point-mutated in the epitopes. Science in China. Series C, Life sciences 11 15382680
2012 Pathway analysis of genome-wide association study for bone mineral density. Molecular biology reports 9 22531938
2004 3D models of yeast RNase P/MRP proteins Rpp1p and Pop3p. RNA (New York, N.Y.) 9 15613537
2018 Crystal structures of the archaeal RNase P protein Rpp38 in complex with RNA fragments containing a K-turn motif. Acta crystallographica. Section F, Structural biology communications 8 29372908
2019 Autoantibodies to a novel Rpp38 (Th/To) derived B-cell epitope are specific for systemic sclerosis and associate with a distinct clinical phenotype. Rheumatology (Oxford, England) 7 31323671
2011 Assembly of the complex between archaeal RNase P proteins RPP30 and Pop5. Archaea (Vancouver, B.C.) 7 22162665
2003 Alterations in the intracellular level of a protein subunit of human RNase P affect processing of tRNA precursors. Nucleic acids research 7 12907726
2005 Regulated expression of functional external guide sequences in mammalian cells using a U6 RNA polymerase III promoter. RNA (New York, N.Y.) 4 16131590
2025 Ribonuclease P/MRP subunit RPP40 coordinates the transcription of pre-rRNA and ribosomal protein genes to promote Hepatocellular carcinoma malignancy. Gene 1 40517827
2019 Genetic Switches between Cancer and Emphysema Resolution of Cigarette-Smoke Induced Inflammation. EC pulmonology and respiratory medicine 1 38116482