Affinage

Showing PRORP — MRPP3 is a alias.

PRORP

Mitochondrial ribonuclease P catalytic subunit · UniProt O15091

Length
583 aa
Mass
67.3 kDa
Annotated
2026-06-10
88 papers in source corpus 27 papers cited in narrative 27 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PRORP (MRPP3) is the metallonuclease subunit of mitochondrial RNase P, the enzyme that removes the 5' leader from precursor tRNAs encoded by the polycistronic mitochondrial transcript, and 5' cleavage by PRORP precedes 3' tRNA processing in vivo and is required for mitochondrial ribosome biogenesis, translation, and respiration (PMID:27498866, PMID:27131785). Catalysis is carried out by a conserved NYN metallonuclease domain tethered to a pentatricopeptide-repeat (PPR) domain through a structural zinc-binding module; conserved active-site aspartates coordinate at least two catalytic Mg2+ ions in a cooperative, two-metal-ion mechanism whose rate-limiting step is deprotonation of a metal-bound water nucleophile (PMID:22991464, PMID:25817998). This mechanism is distinct from RNA-based RNase P in that it does not require direct metal coordination to the pro-Rp oxygen of the scissile phosphate (PMID:22976545). In the human enzyme, isolated PRORP adopts an auto-inhibitory conformation in which the active site is distorted and metal ions are excluded; productive catalysis requires association with the TRMT10C (MRPP1)–SDR5C1 (MRPP2) methyltransferase subcomplex and pre-tRNA, which trigger an induced-fit rearrangement (PMID:25953853, PMID:25928769). The complex assembles only in the presence of pre-tRNA, with TRMT10C-SDR5C1 enveloping the tRNA, recognizing the anticodon loop, and directing PRORP's nuclease domain precisely to the cleavage site via a rigid leader-length "measuring" mechanism (PMID:34489609, PMID:41261864); PRORP's PPR domain independently retains ancestral nanomolar-affinity pre-tRNA binding through the tRNA elbow region and can cleave some substrates at reduced efficiency on its own (PMID:23322041, PMID:37779095). Beyond canonical tRNA processing, PRORP is recruited by WBSCR16 to cleave the 16S rRNA–mt-tRNALeu junction during mitoribosome assembly (PMID:39878214), and its abundance is controlled post-transcriptionally by LON protease-dependent turnover during the mitochondrial unfolded protein response and by N6AMT1-dependent cytosolic translation (PMID:27350246, PMID:39503847). Bi-allelic PRORP variants cause a mitochondrial disease characterized by impaired pre-tRNA processing, transcript accumulation, and reduced mitochondrial protein synthesis, with defects rescued by wild-type PRORP cDNA (PMID:34715011).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2012 High

    Establishing how a protein-only RNase P is built answered whether catalysis and substrate binding are modular, revealing a metallonuclease domain joined to a PPR domain by a zinc module.

    Evidence X-ray crystallography and active-site aspartate mutagenesis of Arabidopsis PRORP1

    PMID:22991464

    Open questions at the time
    • Structure from plant ortholog, not human
    • Did not resolve how partner proteins regulate activity
  2. 2012 High

    Phosphorothioate substrate analysis answered whether PRORP uses the RNA-world catalytic chemistry, showing its metal ions do not coordinate the scissile-phosphate pro-Rp oxygen unlike RNA-based RNase P.

    Evidence Single-turnover kinetics with Rp-phosphorothioate-modified pre-tRNA on Arabidopsis PRORP enzymes

    PMID:22976545

    Open questions at the time
    • Exact geometry of metal-substrate coordination not defined
    • Plant enzyme only
  3. 2013 High

    Footprinting and metal characterization addressed how PRORP recognizes tRNA, showing it reads the elbow/corner region and dispenses with the anticodon, mirroring ribonucleoprotein RNase P.

    Evidence Activity assays, RNA footprinting, SAXS, and zinc-binding analysis of Arabidopsis PRORP1

    PMID:23322041

    Open questions at the time
    • No atomic-resolution enzyme-substrate complex
    • Plant single-subunit enzyme, not human three-protein complex
  4. 2015 High

    Crystal structures of human MRPP3 answered why the isolated human enzyme is inactive, revealing an auto-inhibitory distorted active site that excludes metals until partner- and substrate-driven rearrangement.

    Evidence Independent X-ray crystallography plus biochemical assays of human MRPP3 (two studies)

    PMID:25928769 PMID:25953853

    Open questions at the time
    • Conformation of the activated state not captured
    • Did not visualize partner contacts driving activation
  5. 2015 High

    Kinetic and metal-rescue analysis defined the catalytic mechanism, establishing a cooperative two-Mg2+ mechanism with a rate-limiting nucleophile deprotonation step.

    Evidence Turnover kinetics, metal alteration, Asp-to-Ala metal rescue, and pH dependence of Arabidopsis PRORP1

    PMID:25817998

    Open questions at the time
    • Identity of all metal ligands incomplete
    • Plant ortholog
  6. 2016 High

    In vivo knockout established that MRPP3 is essential and non-redundant and that 5' cleavage precedes 3' processing, linking PRORP to mitoribosome biogenesis.

    Evidence Conditional MRPP3 knockout mice with PARE and RNA-seq

    PMID:27498866

    Open questions at the time
    • Did not resolve molecular coupling to ribosome assembly
    • Tissue-restricted knockout
  7. 2016 Medium

    Drosophila genetics confirmed conservation, showing the three RNase P subunits are each essential, mitochondrially localized, and required for tRNA processing.

    Evidence Drosophila loss-of-function and overexpression genetics with immunofluorescence and tRNA northern blots

    PMID:27131785

    Open questions at the time
    • No biochemical reconstitution in fly system
    • Overexpression morphology phenotype mechanism unclear
  8. 2016 Medium

    Chemical-modification mapping identified the substrate-contacting surface, pinpointing lysines at the tips of PRORP's V-shaped arms as essential for binding and cleavage.

    Evidence Lysine chemical modification, MRM mass spectrometry, and mutagenesis of Arabidopsis PRORP1

    PMID:27166372

    Open questions at the time
    • No co-structure with tRNA confirming contacts
    • Plant enzyme
  9. 2016 High

    Post-translational regulation was uncovered by linking MRPP3 abundance to LON protease turnover during the mitochondrial unfolded protein response.

    Evidence Pharmacological LON inhibition/UPRmt induction with transcriptomics, proteomics, and pre-RNA processing assays

    PMID:27350246

    Open questions at the time
    • Degradation signal/recognition motif on MRPP3 unknown
    • Direct LON-MRPP3 interaction not structurally defined
  10. 2018 Medium

    Assembly studies showed the complex is substrate-induced, only forming in the presence of pre-tRNA, and mapped MRPP1 self-interaction and SAM-binding determinants.

    Evidence Crystallography, interaction and activity assays, and SAXS of the MRPP1-MRPP2-MRPP3 complex

    PMID:29880640

    Open questions at the time
    • Only low-resolution SAXS architecture
    • Stoichiometry inferred, not directly resolved
  11. 2019 Medium

    Reconstitution of human mtRNase P demonstrated cooperative function and substrate selectivity, with mutual stimulation of cleavage and methylation among subunits.

    Evidence In vitro cleavage and methylation assays with purified recombinant mtRNase P on individual pre-tRNAs

    PMID:31455609

    Open questions at the time
    • Basis of substrate selectivity not structurally explained
    • Single-lab reconstitution
  12. 2021 High

    Cryo-EM of the human complex with pre-tRNA answered how PRORP is recruited and activated, showing TRMT10C-SDR5C1 binds the tRNA including the anticodon loop and positions PRORP for precise cleavage.

    Evidence Cryo-EM structure of human mtRNase P bound to precursor tRNA

    PMID:34489609

    Open questions at the time
    • Catalytic transition state not captured
    • Dynamics of induced-fit activation inferred from static structure
  13. 2021 High

    Disease genetics established PRORP as a Mendelian disease gene, with bi-allelic variants causing tRNA processing defects rescued by wild-type cDNA.

    Evidence Patient fibroblast analysis, lentiviral cDNA rescue, and in vitro processing assays with recombinant variants

    PMID:34715011

    Open questions at the time
    • Genotype-phenotype correlation across variants incomplete
    • Tissue-specificity of disease not resolved
  14. 2021 Medium

    A knock-in mouse linked a common MRPP3 variant to metabolic disease, showing N437S causes insulin resistance via reduced mitochondrial calcium and impaired insulin secretion.

    Evidence CRISPR-Cas9 N437S knock-in mice with metabolic phenotyping, calcium measurement, and islet insulin assays

    PMID:34559558

    Open questions at the time
    • Mechanistic link from PRORP variant to mitochondrial calcium is indirect
    • Variant did not markedly alter mitochondrial gene expression, leaving the connection unexplained
  15. 2023 High

    Kinetic dissection of human PRORP alone versus the full complex defined the partner subunits' role, showing PRORP retains nanomolar pre-tRNA binding and intrinsic catalysis while TRMT10C-SDR5C1 directs the nuclease to the correct site.

    Evidence Kinetic cleavage analysis of human PRORP alone vs. full complex across 12 mitochondrial pre-tRNAs

    PMID:37779095

    Open questions at the time
    • Why some substrates are PRORP-cleavable alone and others not is incompletely explained
    • No structure of PRORP-alone cleaving substrate
  16. 2024 High

    Sequential cryo-EM structures placed PRORP within an ordered tRNA maturation pathway and established TRMT10C-SDR5C1 as a folding quality-control checkpoint required for PRORP cleavage.

    Evidence Cryo-EM structures of four mitochondrial tRNA maturation steps

    PMID:38824131

    Open questions at the time
    • Kinetics of step-to-step handoff not measured
    • How checkpoint rejects misfolded tRNAs not defined
  17. 2024 Medium

    Leader-length kinetics defined the cleavage-site selection rule, showing a rigid 'measuring mechanism' that requires TRMT10C-SDR5C1 to contact pre-tRNA to stimulate PRORP and explaining failure to process D-armless tRNASer(AGY).

    Evidence Kinetic analysis with leader-length and acceptor-stem substrate variants of human mtRNase P

    PMID:41261864

    Open questions at the time
    • Structural basis of the ruler not directly visualized
    • Single-lab kinetics
  18. 2024 Medium

    Two regulatory inputs to PRORP abundance were identified: WBSCR16 recruits PRORP to nascent 16S rRNA for ribosome assembly, and N6AMT1 controls cytosolic translation of PRORP mRNA.

    Evidence Adipose-specific Wbscr16 knockout with RIP/co-IP, and N6AMT1 knockout with ribosome profiling and RNA processing assays

    PMID:39503847 PMID:39878214

    Open questions at the time
    • Direct biochemical interaction surfaces not mapped
    • Whether these pathways are tissue-restricted unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the auto-inhibited PRORP active site is structurally remodeled into the catalytically competent metal-loaded state during induced-fit activation, and what governs its broad substrate selectivity in vivo, remain unresolved.
  • No structure of the catalytic transition state of human mtRNase P
  • Determinants of physiological substrate selectivity not fully defined
  • In vivo regulation integrating turnover, recruitment, and translational control not unified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 5 GO:0003723 RNA binding 3 GO:0016787 hydrolase activity 3
Localization
GO:0005739 mitochondrion 2
Pathway
R-HSA-8953854 Metabolism of RNA 3 R-HSA-1852241 Organelle biogenesis and maintenance 2
Partners
LONP1N6AMT1SDR5C1TRMT10CWBSCR16
Complex memberships
mitochondrial RNase P (MRPP1-MRPP2-MRPP3)

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 Crystal structure of Arabidopsis thaliana PRORP1 at 1.75 Å resolution reveals a prototypical metallonuclease (NYN) domain tethered to a pentatricopeptide repeat (PPR) domain by a structural zinc-binding domain. Conserved aspartate residues in the NYN domain are important for catalytic activity and metal binding, and the PPR domain enhances activity through interaction with pre-tRNA. X-ray crystallography (1.75 Å), active-site mutagenesis of aspartate residues, biochemical activity assays Proceedings of the National Academy of Sciences of the United States of America High 22991464
2013 PRORP enzymes (using Arabidopsis PRORP1) bind one zinc atom and use the anticodon domain of tRNA dispensably, while individual residues in D and TψC loops are essential for PRORP function. Footprinting and activity assays indicate tRNA recognition involves the elbow/corner region, analogous to ribonucleoprotein RNase P. Activity assays, RNA footprinting, small-angle X-ray scattering (SAXS), zinc-binding characterization Nature communications High 23322041
2015 Crystal structure of human MRPP3 (PRORP) reveals a distorted, non-productive active site that is auto-inhibitory, with metal ions excluded from the catalytic center. MRPP3 requires association with MRPP1, MRPP2, and pre-tRNA substrate to switch to a productive conformation via an induced-fit mechanism. X-ray crystallography, biochemical activity assays Nucleic acids research High 25953853
2015 Crystal structure of human MRPP3 (PRORP) in a separate study confirms auto-inhibitory conformation. Biochemical assays show that the active site requires rearrangement triggered by additional regulation to allow metal ion entry and catalytic activity. X-ray crystallography, biochemical assays Scientific reports High 25928769
2015 Mechanistic studies of Arabidopsis PRORP1 reveal that catalysis involves at least two active-site magnesium ions (cooperative Mg2+ dependence, nH=2), that two aspartate residues enhance metal ion affinity (identified by metal rescue of Asp-to-Ala mutations), and that a single ionization (pKa ~8.7) consistent with deprotonation of a metal-bound water nucleophile is rate-limiting. The pH and metal dependence mirrors that of RNA-based RNase P, indicating similar catalytic mechanisms. Multiple and single turnover kinetics, metal ion alteration experiments, active-site mutagenesis with metal rescue, pH dependence analysis The Journal of biological chemistry High 25817998
2012 Arabidopsis PRORP enzymes (PRORP1, 2, 3) process pre-tRNA 5' ends via a mechanism that is largely insensitive to Rp-phosphorothioate modification at the cleavage site (affected ≤5-fold, versus 3 orders of magnitude inhibition for bacterial RNA-based RNase P), indicating that PRORP catalysis does not involve direct metal ion coordination to the pro-Rp oxygen of the scissile phosphate, unlike RNA-based RNase P. Kinetic analysis with phosphorothioate-modified pre-tRNA substrates under single-turnover conditions Chembiochem : a European journal of chemical biology High 22976545
2016 Conditional knockout of MRPP3 (PRORP) in mouse heart and skeletal muscle demonstrates that MRPP3 is essential for life and its activity is non-redundant. In vivo, 5' tRNA cleavage by MRPP3 precedes 3' tRNA processing. Loss of MRPP3 disrupts mitochondrial ribosomal subunit biogenesis, which proceeds co-transcriptionally, with large mitoribosomal proteins forming subcomplexes on unprocessed RNA containing the 16S rRNA. Conditional knockout mice, transcriptome-wide PARE (parallel analysis of RNA ends), RNA-seq Cell reports High 27498866
2016 MRPP3 (PRORP) is subject to LON protease-dependent turnover during mitochondrial unfolded protein response (UPRmt). Acute inhibition of LON protease leads to MRPP3 accumulation; pharmacological induction of UPRmt causes transcriptional repression and LON-dependent turnover of MRPP3, resulting in pre-RNA processing defects in the mitochondrial matrix. Pharmacological inhibition, global transcriptomics, proteomics, functional pre-RNA processing assays Nature High 27350246
2021 Cryo-EM structure of human mitochondrial RNase P bound to precursor tRNA reveals: TRMT10C (MRPP1) and SDR5C1 (MRPP2) form a subcomplex that binds conserved mitochondrial tRNA elements including the anticodon loop and positions the tRNA for methylation; PRORP (MRPP3) is recruited and activated through interactions with its PPR and nuclease domains to ensure precise pre-tRNA cleavage. This reveals a unique mechanism of substrate recognition and processing. Cryo-EM structure determination Nature structural & molecular biology High 34489609
2024 Cryo-EM structures capturing four steps of mitochondrial tRNA maturation (5' processing, 3' processing, methylation, and 3'-CCA addition) show that the TRMT10C-SDR5C1 methyltransferase subcomplex recognizes pre-tRNA in a distinct mode supporting tRNA-end processing, and can serve as a tRNA-folding quality-control checkpoint before sequential docking of maturation enzymes including PRORP. The methyltransferase subcomplex is required for PRORP cleavage activity. Cryo-EM structural determination of four distinct complexes Nature communications High 38824131
2018 The MRPP1-MRPP2-MRPP3 RNase P complex only assembles in the presence of precursor tRNA. The MRPP1 N terminus is involved in tRNA binding and monomer-monomer self-interaction; the C-terminal SPOUT fold contains key residues for SAM binding and N1-methylation. Low-resolution SAXS models suggest overall architecture, stoichiometry, and orientation of subunits. X-ray crystallography, interaction assays, activity assays, SAXS The Journal of biological chemistry Medium 29880640
2011 MRPP1 and MRPP3 together process the 5' ends of mitochondrial tRNAs and the 5' unconventional non-tRNA-containing site of the CO1 transcript. MRPP1 is essential for transcript processing, RNA modification, translation, and mitochondrial respiration. ELAC2 and PTCD1 affect 3' end processing of tRNAs. Deep sequencing of mitochondrial RNA 5' and 3' ends, siRNA knockdown of individual components Cell cycle (Georgetown, Tex.) Medium 21857155
2014 HSD10 (MRPP2/SDR5C1) is important for maintaining normal MRPP1 protein levels; knockdown of HSD10 reduces MRPP1 protein but not MRPP3 protein. Loss of HSD10 impairs processing of precursor tRNA transcripts from the mitochondrial heavy strand. Ectopic expression of HSD10 partially restores RNA processing and MRPP1 expression, demonstrating that HSD10 maintains the MRPP1-HSD10 subcomplex of RNase P. HSD10 knockdown, patient fibroblast analysis, ectopic expression rescue, RT-PCR/northern blot for RNA processing Human molecular genetics Medium 24549042
2021 Bi-allelic variants in PRORP cause mitochondrial tRNA processing defects. Patient fibroblasts show decreased PRORP protein, accumulation of unprocessed mitochondrial transcripts, and decreased levels of mitochondrially encoded proteins. Wild-type PRORP cDNA rescues these defects. Recombinant disease-associated variants show diminished mitochondrial tRNA processing in mt-RNase P processing assays. Patient fibroblast analysis, lentiviral cDNA rescue, in vitro mt-tRNA processing assays with recombinant proteins American journal of human genetics High 34715011
2019 Purified human mtRNase P (containing MRPP3/PRORP) recognizes, cleaves, and methylates some but not all mitochondrial pre-tRNAs in vitro, indicating substrate selectivity. Addition of SAM (the MRPP1 cofactor) enhances binding and cleavage of some pre-tRNAs. Conversely, presence of MRPP3 enhances the methylation activity of MRPP1/2. The subunits work cooperatively for efficient recognition, processing, and methylation. In vitro cleavage and methylation assays with purified recombinant mtRNase P and individual pre-tRNA substrates RNA (New York, N.Y.) Medium 31455609
2023 Kinetic analysis shows that human PRORP alone binds mitochondrial pre-tRNAs with nanomolar affinity and can cleave some substrates at reduced efficiency without TRMT10C and SDR5C1, indicating its PPR domain retains ancestral pre-tRNA binding and its metallonuclease domain is functional. The main function of TRMT10C-SDR5C1 is to direct PRORP's nuclease domain to the cleavage site, increasing rate and accuracy of cleavage — especially important due to erosion of canonical structural features in mitochondrial tRNAs. Kinetic cleavage analysis of human PRORP alone vs. full complex with 12 different mitochondrial pre-tRNAs Nucleic acids research High 37779095
2016 Loss-of-function of Drosophila PRORP ortholog (Mulder) causes lethality, aberrant mitochondrial tRNA processing, and mitochondrial dysfunction. Each of the three mt-RNase P subunits (Mulder/PRORP, Scully/MRPP2, Roswell/MRPP1) is essential and localizes to mitochondria. Overexpression of PRORP/Mulder causes abnormal mitochondrial morphology. Drosophila genetics (loss-of-function, overexpression), immunofluorescence localization, mitochondrial tRNA northern blots Nucleic acids research Medium 27131785
2016 The Arabidopsis PRORP3 nuclear single-subunit PRORP requires a larger portion of intact tRNA structure for substrate recognition compared to bacterial RNA-based RNase P, requires the leader to be single-stranded, and cleavage site depends on combined dimensions of acceptor stem and T domain. It makes little to no contacts with the 5' or 3' extensions beyond substrate body. Comprehensive substrate recognition analysis using variant pre-tRNAs in cleavage assays Nucleic acids research Medium 26896801
2015 Crystal structure of Arabidopsis PRORP2 (nuclear isoform) at 3.2 Å reveals an overall V-shaped protein with conserved metallonuclease active-site structure. PRORP2 requires Mg2+ for catalysis and cleaves nuclear-encoded substrates up to 10-fold faster than mitochondrial-encoded pre-tRNA under single-turnover conditions. Pre-tRNA leader and trailer lengths do not significantly alter observed rate constants. X-ray crystallography (3.2 Å), single-turnover cleavage assays, metal ion dependence measurements Journal of molecular biology High 26655022
2016 Lysines at the tips of PRORP1's V-shaped arms (in the first PPR motif and in the NYN domain proximal to the catalytic center) are substrate-contacting residues essential for binding and cleaving pre-tRNA, established by chemical modification mass spectrometry followed by site-directed mutagenesis and biochemical validation. Chemical modification of lysines, multiple-reaction monitoring mass spectrometry, site-directed mutagenesis, biochemical activity assays Nucleic acids research Medium 27166372
2020 Eleven disease-linked mutations in mitochondrial pre-tRNAIle, pre-tRNALeu(UUR), and pre-tRNAMet weaken pre-tRNA binding affinity for mtRNase P (2- to 6-fold) and decrease 5' end processing (up to ~55% reduction) and methylation activity (up to ~90% reduction) by mtRNase P. Mutations in pre-tRNALeu(UUR) alter tRNA fold, contributing to partial loss of mtRNase P function. In vitro binding and cleavage assays with recombinant mtRNase P and disease-mutant pre-tRNAs RNA (New York, N.Y.) Medium 33380464
2021 A common MRPP3 N437S missense variant introduced by CRISPR-Cas9 into mice causes insulin resistance on high-fat diet. The variant reduced mitochondrial calcium levels, lowering insulin release from pancreatic islet β cells, resulting in lower insulin levels, imbalanced metabolism, and liver steatosis. The variant did not markedly influence mitochondrial gene expression. CRISPR-Cas9 knock-in mouse model, metabolic phenotyping, mitochondrial calcium measurements, pancreatic islet insulin secretion assays Science advances Medium 34559558
2024 Kinetic analysis of human mtRNase P shows that processing efficiency increases with 5' leader length and decreases sharply at a leader length of 1 nt. MtRNase P uses a rigid 'measuring mechanism' for cleavage-site selection. TRMT10C-SDR5C1 must interact with the pre-tRNA (not just PRORP) to stimulate PRORP cleavage; without pre-tRNA interactions, TRMT10C-SDR5C1 cannot stimulate PRORP. This explains why mtRNase P is unable to process the D-armless mitochondrial tRNASer(AGY). Kinetic analysis using substrate and protein variants, specific leader-length and acceptor-stem extension variants Nucleic acids research Medium 41261864
2024 WBSCR16 recruits MRPP3 (PRORP) to nascent 16S rRNA and assists in cleavage of the 16S rRNA-mt-tRNALeu junction, facilitating 16S rRNA processing and mitochondrial ribosome assembly in mammals. Adipose-specific Wbscr16 knockout mice, RNA immunoprecipitation, co-immunoprecipitation, RNA processing assays Nucleic acids research Medium 39878214
2024 N6AMT1, a nucleo-cytosolic methyltransferase, is required for cytosolic translation of MRPP3 (PRORP) mRNA. Loss of N6AMT1 or its catalytic activity reduces PRORP protein levels, impairing mitochondrial RNA processing (accumulation of unprocessed and double-stranded RNA) and preventing mitochondrial protein synthesis. N6AMT1 knockout/catalytic mutant, transcriptional and translational profiling (ribosome profiling), mitochondrial RNA processing assays Proceedings of the National Academy of Sciences of the United States of America Medium 39503847
2022 Gambogic acid is a rapid-binding uncompetitive inhibitor of PRORP1 that targets the PRORP1-substrate complex. Juglone acts as a time-dependent inhibitor forming a covalent adduct with cysteine residues on the surface of PRORP1, as confirmed by X-ray crystal structures of the PRORP1-juglone complex. Both compounds similarly inhibit human mtRNase P and are 50-fold less potent against bacterial RNA-based RNase P. High-throughput fluorescence polarization cleavage assay, kinetic inhibitor characterization, X-ray crystallography of PRORP1-juglone complex The Journal of biological chemistry High 36370850
2016 A missense mutation in MRPP3 explains ~22% of the variance in posttranscriptional modification of functionally important sites in mitochondrial tRNAs across ~1000 individuals, representing a major nuclear genetic determinant of mt-tRNA modification. Genome-wide association study with ultra-deep mitochondrial RNA sequencing (>6000×) in ~1000 individuals Science (New York, N.Y.) Low 24763589

Source papers

Stage 0 corpus · 88 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 Mitochondrial unfolded protein response controls matrix pre-RNA processing and translation. Nature 254 27350246
2011 RNA processing in human mitochondria. Cell cycle (Georgetown, Tex.) 201 21857155
1992 Evidence for processivity and two-step binding of the RNA substrate from studies of J1/2 mutants of the Tetrahymena ribozyme. Biochemistry 127 1736996
1997 RNA hydration: three nanoseconds of multiple molecular dynamics simulations of the solvated tRNA(Asp) anticodon hairpin. Journal of molecular biology 123 9199403
2016 Hierarchical RNA Processing Is Required for Mitochondrial Ribosome Assembly. Cell reports 121 27498866
1993 Substrate-assisted catalysis in the cleavage of DNA by the EcoRI and EcoRV restriction enzymes. Proceedings of the National Academy of Sciences of the United States of America 113 8378323
2012 Mitochondrial ribonuclease P structure provides insight into the evolution of catalytic strategies for precursor-tRNA 5' processing. Proceedings of the National Academy of Sciences of the United States of America 96 22991464
2011 Of P and Z: mitochondrial tRNA processing enzymes. Biochimica et biophysica acta 94 22137969
2016 Recessive Mutations in TRMT10C Cause Defects in Mitochondrial RNA Processing and Multiple Respiratory Chain Deficiencies. American journal of human genetics 86 27132592
1991 Binding and cleavage of nucleic acids by the "hairpin" ribozyme. Biochemistry 86 1909564
2021 Structural basis of RNA processing by human mitochondrial RNase P. Nature structural & molecular biology 81 34489609
2014 High-resolution genomic analysis of human mitochondrial RNA sequence variation. Science (New York, N.Y.) 80 24763589
1997 Ribonuclease P catalysis requires Mg2+ coordinated to the pro-RP oxygen of the scissile bond. Biochemistry 70 9054547
2015 Distribution of Ribonucleoprotein and Protein-Only RNase P in Eukarya. Molecular biology and evolution 66 26341299
2013 Structural insights into protein-only RNase P complexed with tRNA. Nature communications 61 23322041
2000 Stereochemical outcome and kinetic effects of Rp- and Sp-phosphorothioate substitutions at the cleavage site of vaccinia type I DNA topoisomerase. Biochemistry 57 10820030
2014 Mutation or knock-down of 17β-hydroxysteroid dehydrogenase type 10 cause loss of MRPP1 and impaired processing of mitochondrial heavy strand transcripts. Human molecular genetics 53 24549042
2016 The Diversity of Ribonuclease P: Protein and RNA Catalysts with Analogous Biological Functions. Biomolecules 52 27187488
2015 Structure of the nuclease subunit of human mitochondrial RNase P. Nucleic acids research 50 25953853
2007 Mapping of the functional phosphate groups in the catalytic core of deoxyribozyme 10-23. The FEBS journal 49 17250742
2021 Bi-allelic variants in the mitochondrial RNase P subunit PRORP cause mitochondrial tRNA processing defects and pleiotropic multisystem presentations. American journal of human genetics 46 34715011
2009 Separation of RNA phosphorothioate oligonucleotides by HPLC. Methods in enzymology 46 20946775
2002 Evidence for a polynuclear metal ion binding site in the catalytic domain of ribonuclease P RNA. The EMBO journal 43 11980722
2013 PPR proteins shed a new light on RNase P biology. RNA biology 39 23925311
2011 Hydroxysteroid (17β) dehydrogenase X in human health and disease. Molecular and cellular endocrinology 39 21708223
2017 Novel patient missense mutations in the HSD17B10 gene affect dehydrogenase and mitochondrial tRNA modification functions of the encoded protein. Biochimica et biophysica acta. Molecular basis of disease 38 28888424
1993 The stereochemical course of the first step of pre-mRNA splicing. Nucleic acids research 35 8265362
2018 Immunochip Meta-Analysis of Inflammatory Bowel Disease Identifies Three Novel Loci and Four Novel Associations in Previously Reported Loci. Journal of Crohn's & colitis 34 29584801
2000 Evidence for an RNA-based catalytic mechanism in eukaryotic nuclear ribonuclease P. RNA (New York, N.Y.) 33 10786846
2018 Structural insight into the human mitochondrial tRNA purine N1-methyltransferase and ribonuclease P complexes. The Journal of biological chemistry 32 29880640
2016 Substrate recognition and cleavage-site selection by a single-subunit protein-only RNase P. Nucleic acids research 31 26896801
2015 Mechanistic Studies Reveal Similar Catalytic Strategies for Phosphodiester Bond Hydrolysis by Protein-only and RNA-dependent Ribonuclease P. The Journal of biological chemistry 31 25817998
2000 Mechanism of RNase T1: concerted triester-like phosphoryl transfer via a catalytic three-centered hydrogen bond. Chemistry & biology 31 11048955
2024 Structural basis for human mitochondrial tRNA maturation. Nature communications 30 38824131
2015 Auto-inhibitory Mechanism of the Human Mitochondrial RNase P Protein Complex. Scientific reports 30 25928769
2012 tRNA processing by protein-only versus RNA-based RNase P: kinetic analysis reveals mechanistic differences. Chembiochem : a European journal of chemical biology 30 22976545
2000 Effects of phosphorothioate modifications on precursor tRNA processing by eukaryotic RNase P enzymes. Journal of molecular biology 30 10788319
2013 RNase P enzymes: divergent scaffolds for a conserved biological reaction. RNA biology 29 23595059
2020 Analysis of mitochondrial m1A/G RNA modification reveals links to nuclear genetic variants and associated disease processes. Communications biology 28 32221480
2020 Old and New Concepts in Ubiquitin and NEDD8 Recognition. Biomolecules 28 32272761
2017 A Silver-Specific DNAzyme with a New Silver Aptamer and Salt-Promoted Activity. Biochemistry 27 28345892
2015 Genome-wide association study of leukotriene modifier response in asthma. The pharmacogenomics journal 27 26031901
2004 Ca2+ binding in the active site of HincII: implications for the catalytic mechanism. Biochemistry 27 15491133
2015 Nuclear Protein-Only Ribonuclease P2 Structure and Biochemical Characterization Provide Insight into the Conserved Properties of tRNA 5' End Processing Enzymes. Journal of molecular biology 26 26655022
2014 Molecular characterization of three PRORP proteins in the moss Physcomitrella patens: nuclear PRORP protein is not essential for moss viability. PloS one 26 25272157
2016 Differential substrate recognition by isozymes of plant protein-only Ribonuclease P. RNA (New York, N.Y.) 25 26966150
2016 Loss of the mitochondrial protein-only ribonuclease P complex causes aberrant tRNA processing and lethality in Drosophila. Nucleic acids research 23 27131785
2011 Ground-state coordination of a catalytic metal to the scissile phosphate of a tertiary-stabilized Hammerhead ribozyme. RNA (New York, N.Y.) 23 22124015
2019 Interplay between substrate recognition, 5' end tRNA processing and methylation activity of human mitochondrial RNase P. RNA (New York, N.Y.) 21 31455609
2004 NMR-based reappraisal of the coordination of a metal ion at the pro-Rp oxygen of the A9/G10.1 site in a hammerhead ribozyme. Journal of the American Chemical Society 20 15563179
2004 Mechanistic insights from the structures of HincII bound to cognate DNA cleaved from addition of Mg2+ and Mn2+. Journal of molecular biology 19 15476804
2017 Protein-only RNase P function in Escherichia coli: viability, processing defects and differences between PRORP isoenzymes. Nucleic acids research 18 28499021
2009 Haplotypes encompassing the KIAA0391 and PSMA6 gene cluster confer a genetic link for myocardial infarction and coronary artery disease. Annals of human genetics 18 19624571
2023 Cleavage kinetics of human mitochondrial RNase P and contribution of its non-nuclease subunits. Nucleic acids research 17 37779095
2021 A common genetic variant of a mitochondrial RNA processing enzyme predisposes to insulin resistance. Science advances 16 34559558
2019 Involvement of PIN-like domain nucleases in tRNA processing and translation regulation. IUBMB life 15 31066520
2016 Use of chemical modification and mass spectrometry to identify substrate-contacting sites in proteinaceous RNase P, a tRNA processing enzyme. Nucleic acids research 15 27166372
2022 Structural and mechanistic basis of RNA processing by protein-only ribonuclease P enzymes. Trends in biochemical sciences 14 35725940
2021 Minimal protein-only RNase P structure reveals insights into tRNA precursor recognition and catalysis. The Journal of biological chemistry 14 34339732
2020 Disease-associated mutations in mitochondrial precursor tRNAs affect binding, m1R9 methylation, and tRNA processing by mtRNase P. RNA (New York, N.Y.) 14 33380464
2023 Controlled sulfur-based engineering confers mouldability to phosphorothioate antisense oligonucleotides. Nucleic acids research 13 37099382
2022 Crystal structures and insights into precursor tRNA 5'-end processing by prokaryotic minimal protein-only RNase P. Nature communications 13 35484139
2018 Visit-to-visit lipid variability: Clinical significance, effects of lipid-lowering treatment, and (pharmaco) genetics. Journal of clinical lipidology 13 29422286
2018 Two symmetric arginine residues play distinct roles in Thermus thermophilus Argonaute DNA guide strand-mediated DNA target cleavage. Proceedings of the National Academy of Sciences of the United States of America 13 30591565
2004 Microsatellite genotyping of chromosome 14q13.2-14q13 in the vicinity of proteasomal gene PSMA6 and association with Graves' disease in the Latvian population. Immunogenetics 13 15205934
2021 The Dynamic Network of RNP RNase P Subunits. International journal of molecular sciences 12 34638646
2016 Mechanistic and Structural Studies of Protein-Only RNase P Compared to Ribonucleoproteins Reveal the Two Faces of the Same Enzymatic Activity. Biomolecules 11 27348014
2024 Discovery, structure, mechanisms, and evolution of protein-only RNase P enzymes. The Journal of biological chemistry 9 38336295
2017 Activation of the glmS Ribozyme Nucleophile via Overdetermined Hydrogen Bonding. Biochemistry 9 28787138
2006 Synthesis, characterization, and biological properties of small branched RNA fragments containing chiral (Rp and Sp) 2',5'-phosphorothioate linkages. Nucleosides, nucleotides & nucleic acids 9 16541962
2022 Gambogic acid and juglone inhibit RNase P through distinct mechanisms. The Journal of biological chemistry 8 36370850
2010 Identification of a novel candidate locus for juvenile idiopathic arthritis at 14q13.2 in the Latvian population by association analysis with microsatellite markers. DNA and cell biology 8 20136554
2024 Cytosolic N6AMT1-dependent translation supports mitochondrial RNA processing. Proceedings of the National Academy of Sciences of the United States of America 7 39503847
2024 Multiple structural flavors of RNase P in precursor tRNA processing. Wiley interdisciplinary reviews. RNA 5 38479802
2022 Identification of human mitochondrial RNA cleavage sites and candidate RNA processing factors. BMC biology 5 35869520
2024 Delayed Diagnosis of Perrault Syndrome: A Rare Genetic Disorder. Case reports in medicine 4 38249302
2022 Reduction of Drosophila Mitochondrial RNase P in Skeletal and Heart Muscle Causes Muscle Degeneration, Cardiomyopathy, and Heart Arrhythmia. Frontiers in cell and developmental biology 4 35663400
2016 17β-Hydroxysteroid dehydrogenase type 10 predicts survival of patients with colorectal cancer and affects mitochondrial DNA content. Cancer letters 4 26884257
2001 Specific metal-ion binding sites in a model of the P4-P6 triple-helical domain of a group I intron. RNA (New York, N.Y.) 4 11497430
1995 Recent approaches to probe functional groups in ribonuclease P RNA by modification interference. Molecular biology reports 4 8901505
2022 Synthetic riboswitches for the analysis of tRNA processing by eukaryotic RNase P enzymes. RNA (New York, N.Y.) 3 35022261
2025 WBSCR16 is essential for mitochondrial 16S rRNA processing in mammals. Nucleic acids research 2 39878214
2024 The protein-only RNase Ps, endonucleases that cleave pre-tRNA: Biological relevance, molecular architectures, substrate recognition and specificity, and protein interactomes. Wiley interdisciplinary reviews. RNA 2 38453211
2024 Comprehensive functional interrogation of susceptibility loci in GWASs identified KIAA0391 as a novel oncogenic driver via regulating pyroptosis in NSCLC. Cancer letters 1 38262497
2026 Hypusination of the translation factor eIF5A regulates mitochondrial tRNA processing to promote prostate cancer aggressiveness. Nature communications 0 41826300
2025 Estimating the 5-Year Publication Potential for Grant Awardees: Analysis of the Peer Reviewed Orthopaedic Research Program. Military medicine 0 40333012
2025 RNase P generated tRFSer-GCT promotes fat storage in adipocytes via Adrb2 signaling. The Journal of biological chemistry 0 41101502
2025 Substrate and enzyme determinants for recognition by human mitochondrial RNase P. Nucleic acids research 0 41261864

Missed literature

Know a paper Affinage missed for PRORP? Flag it for the maintainers and the community.

No submissions yet.