Affinage

PTCD3

Small ribosomal subunit protein mS39 · UniProt Q96EY7

Round 2 corrected
Length
689 aa
Mass
78.5 kDa
Annotated
2026-04-28
54 papers in source corpus 13 papers cited in narrative 13 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PTCD3 (mS39/MRPS39) is a pentatricopeptide repeat-containing structural component of the mitochondrial ribosomal small subunit that forms the mRNA entry channel and serves as the docking platform through which the LRPPRC–SLIRP complex delivers mitochondrial mRNAs for translation (PMID:25838379, PMID:32812867, PMID:39134711). Loss of PTCD3 causes a generalized mitochondrial translation defect with severely reduced Complex I and IV levels and activities, impaired oxidative phosphorylation, and decreased ATP biosynthesis, and biallelic loss-of-function variants cause Leigh syndrome in humans (PMID:19427859, PMID:30607703, PMID:36450274). The Drosophila ortholog is essential for viability, confirming a conserved requirement for mitochondrial function in vivo (PMID:38074476). In colorectal cancer cells, PTCD3 additionally stabilizes SLC38A2 mRNA in an IGF2BP2-dependent manner, promoting glutaminolysis and tumor growth (PMID:40304977).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2009 High

    Establishing that PTCD3 is a mitoribosome-associated protein required for mitochondrial translation resolved its functional context as translational rather than RNA-processing machinery.

    Evidence siRNA knockdown in 143B cells with mitochondrial translation assays, respiration measurements, and sucrose gradient co-sedimentation with the small mitoribosomal subunit

    PMID:19427859

    Open questions at the time
    • Precise position within the mitoribosome unknown
    • No structural data to explain how PTCD3 participates in translation
  2. 2011 Medium

    Cross-linking and affinity purification studies placed PTCD3 at the IF3mt binding site on the small subunit and revealed RNA-mediated association with the mitochondrial transcription elongation machinery, linking it to mRNA handling.

    Evidence Chemical cross-linking to IF3mt with mass spectrometry; affinity purification of TEFM complex with RNase controls

    PMID:21278163 PMID:22015679

    Open questions at the time
    • Whether the TEFM-PTCD3 interaction has functional significance beyond co-sedimentation on RNA
    • No direct mRNA-binding activity demonstrated
  3. 2013 High

    Formal designation of PTCD3 as MRPS39 by ribosome proteomics confirmed its identity as a bona fide mitoribosomal small subunit protein.

    Evidence Mass spectrometry-based ribosome proteomics with siRNA knockdown validation

    PMID:23908630

    Open questions at the time
    • Structural position within the subunit still unresolved
  4. 2015 High

    High-resolution cryo-EM of the intact human mitoribosome revealed the structural position of mS39/PTCD3 among the mitochondria-specific ribosomal proteins of the small subunit.

    Evidence Single-particle cryo-EM at 3.5 Å resolution

    PMID:25838379

    Open questions at the time
    • Functional role in mRNA recruitment not yet defined structurally
    • No visualization of mRNA delivery complexes
  5. 2019 High

    Identification of biallelic PTCD3 variants as the cause of Leigh syndrome with combined OXPHOS deficiency established the gene's clinical relevance and demonstrated that loss of mS39 destabilizes the entire small mitoribosomal subunit.

    Evidence Exome sequencing, patient fibroblast OXPHOS assays, quantitative proteomics, and complementation rescue

    PMID:30607703

    Open questions at the time
    • Limited to a single family; allelic spectrum not defined
    • Mechanism by which loss of one subunit destabilizes the entire small subunit unclear
  6. 2020 High

    Cryo-EM of functional mitoribosome complexes revealed that mS39 forms a dedicated platform in the mRNA entry channel through which the LRPPRC–SLIRP module delivers mt-mRNA, providing a structural mechanism for mRNA loading.

    Evidence Cryo-EM (~3.0 Å) of human mitoribosome with mt-mRNA, mt-tRNAs, and LRPPRC–SLIRP bound

    PMID:32812867

    Open questions at the time
    • Whether mS39 directly contacts mRNA or functions solely as a scaffold for LRPPRC not fully resolved
    • No mutational validation of the mRNA delivery interface
  7. 2022 High

    Replication in additional unrelated Leigh syndrome families with complementation rescue and splicing assays solidified PTCD3 as a Leigh syndrome gene and showed that many pathogenic variants act through aberrant mRNA splicing.

    Evidence WES, minigene splicing assays, high-resolution respirometry, and complementation in patient fibroblasts across two unrelated families

    PMID:36450274

    Open questions at the time
    • Genotype–phenotype correlation across variant types not established
    • No animal model of disease
  8. 2024 High

    Atomic-resolution cryo-EM of the LRPPRC–SLIRP–mRNA–mitoribosome complex defined the molecular contacts between LRPPRC helical repeats and mS39/mS31, establishing the structural basis for mRNA handoff.

    Evidence Cryo-EM with ribosome profiling and metabolic labeling validation

    PMID:39134711

    Open questions at the time
    • Kinetics and regulation of the mRNA handoff process unknown
    • Whether different mt-mRNAs use the same delivery mechanism not tested
  9. 2025 Medium

    An unexpected extra-ribosomal function was reported in colorectal cancer, where PTCD3 stabilizes SLC38A2 mRNA via IGF2BP2 to drive glutaminolysis and tumor growth, broadening its functional repertoire beyond mitochondrial translation.

    Evidence Co-IP, RIP, dual-luciferase assays, siRNA knockdown, and xenograft mouse model in CRC cells

    PMID:40304977

    Open questions at the time
    • Single-lab finding; independent replication needed
    • Whether this mRNA-stabilizing function operates outside cancer contexts unknown
    • Mechanistic relationship between the ribosomal and mRNA-stabilizing roles not addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the precise molecular contacts between mS39 and mt-mRNA during entry-channel loading, whether mS39 has mRNA-selectivity, the basis for tissue-specific vulnerability (brain, in Leigh syndrome), and whether the extra-ribosomal mRNA-stabilizing role in cancer reflects a general moonlighting function.
  • No in vivo mammalian knockout model
  • No structure of pathogenic mS39 missense variants in the ribosomal context
  • Tissue-specific expression and requirement not systematically studied

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 5 GO:0003723 RNA binding 3
Localization
GO:0005739 mitochondrion 7 GO:0005840 ribosome 6
Pathway
R-HSA-392499 Metabolism of proteins 5 R-HSA-1430728 Metabolism 4 R-HSA-1643685 Disease 3
Partners
DHX30IF3MTIGF2BP2LRPPRCMS31SLIRP
Complex memberships
mitochondrial small ribosomal subunit (28S mt-SSU)

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 PTCD3 is a mitochondrial protein that associates with the small subunit of mitochondrial ribosomes. Knockdown of PTCD3 in 143B osteosarcoma cells decreased mitochondrial protein synthesis, mitochondrial respiration, and the activity of Complexes III and IV, without affecting mitochondrial mRNA levels, indicating a role in mitochondrial translation rather than RNA processing/stability. Subcellular fractionation, mitoribosome co-sedimentation, siRNA knockdown with mitochondrial translation and respiration assays FEBS letters High 19427859
2011 PTCD3 was identified as a component of a mitochondrial complex containing TEFM (transcription elongation factor), mitochondrial RNA polymerase (POLRMT), mitochondrial transcripts, and DHX30, recovered by affinity purification from human mitochondria; after RNase treatment PTCD3 was no longer associated with TEFM, indicating the interaction is RNA-mediated. Affinity purification of TEFM from human mitochondria followed by mass spectrometry; RNase treatment controls Nucleic acids research Medium 21278163
2011 PTCD3 (referred to as Pet309 homolog) was identified as a small subunit ribosomal protein by chemical cross-linking to mitochondrial translation initiation factor IF3mt, mapping it to the IF3mt binding site on the small mitoribosomal subunit. Chemical cross-linking of IF3mt to mitoribosome small subunit followed by mass spectrometry identification Biochimica et biophysica acta Medium 22015679
2013 PTCD3 was formally designated MRPS39 (mitochondrial ribosomal protein, small subunit 39) and confirmed as a component of the mitoribosome small subunit; siRNA knockdown demonstrated its essential role in mitochondrial protein synthesis. Mass spectrometry-based ribosome proteomics, siRNA knockdown with mitochondrial translation readout Frontiers in physiology High 23908630
2015 The cryo-EM structure of the intact human mitoribosome at 3.5 Å resolution placed PTCD3/MRPS39 within the small subunit, revealing its structural position among the 36 mitochondria-specific ribosomal proteins. Single-particle cryo-electron microscopy at 3.5 Å resolution Science High 25838379
2016 PTCD3/Ptcd3 was identified as essential for maintenance of Myc-driven B-cell lymphomas in an in vivo reverse-genetic screen; Ptcd3 knockdown in lymphoma cells impaired mitochondrial translation, reduced respiratory activity, and decreased tumor cell survival, establishing it as a Myc-induced metabolic dependency. In vivo RNAi reverse-genetic screen in mouse B-cell lymphomas; mitochondrial respiration and cell survival assays Oncotarget Medium 27635472
2019 Biallelic loss-of-function variants in PTCD3 cause Leigh syndrome with combined OXPHOS deficiency (markedly reduced Complexes I and IV levels and activities, impaired oxygen consumption and ATP biosynthesis, and generalized mitochondrial translation defects). Complementation with wild-type PTCD3 in patient fibroblasts rescued Complex I and IV levels/activities, ATP biosynthesis, and MT-RNR1 rRNA levels, providing functional validation. Quantitative proteomics showed reduced levels of small mitoribosomal subunit proteins. Exome sequencing, patient fibroblast functional studies (OXPHOS enzyme activities, oxygen consumption, ATP biosynthesis, translation), quantitative proteomics, complementation rescue experiments Neurogenetics High 30607703
2020 Cryo-EM structure of the human mitoribosome revealed that PTCD3/mS39 forms a dedicated platform on the mitoribosomal small subunit through which the LRPPRC-SLIRP trans-acting module delivers mt-mRNA, identifying mS39 as a key component of the mRNA entry channel. Cryo-EM structures (~3.0 Å) of human mitoribosome functional complexes including mt-mRNA, mt-tRNAs, and LRPPRC-SLIRP eLife High 32812867
2022 Three additional patients from two unrelated families with biallelic PTCD3 variants presented with Leigh syndrome; PTCD3 protein was significantly reduced in patient fibroblasts, and OXPHOS complexes I and IV subunit steady-state levels and activities were severely decreased. Complementation with wild-type PTCD3 restored complex levels and mitochondrial respiratory capacity, confirming pathogenicity. Minigene assays showed that three of the four variants caused aberrant mRNA splicing. WES, RNA-seq, RT-PCR minigene splicing assays, western blot, OXPHOS enzyme activity, high-resolution respirometry, complementation studies in immortalized fibroblasts Brain pathology High 36450274
2024 Cryo-EM structure of LRPPRC-SLIRP in complex with mRNA and the mitoribosome showed that LRPPRC associates with mitoribosomal proteins mS39 (PTCD3) and the N-terminus of mS31 through recognition of LRPPRC helical repeats, forming a corridor for mRNA handoff to the mitoribosome; mS39 is part of the mRNA entry channel of the small subunit. Cryo-EM structure of LRPPRC-SLIRP-mRNA-mitoribosome complex; RNA sequencing, metabolic labeling, mitoribosome profiling Nature structural & molecular biology High 39134711
2024 Clinical expansion of PTCD3 deficiency confirmed that the PTCD3 gene product forms the entry channel of the mitoribosomal small subunit and binds single-stranded mRNA; a missense variant (His269Tyr) modelled in silico showed minimal structural perturbation, while a nonsense variant (Tyr394Ter) ablates the C-terminal half of the protein. RT-PCR confirmed exon skipping caused by a splice-site variant (c.538+4A>G). Basal respiration was significantly reduced in patient-derived cells. WGS/WES, RT-PCR splicing assay, in silico structural modelling, respirometry in patient fibroblasts JIMD reports Medium 39544688
2023 Loss-of-function of the Drosophila melanogaster ortholog of PTCD3 (CG4679) causes lethality at the second instar, with reduced expression of mitochondrial function and ribosome biogenesis genes and upregulation of neuronal development genes, demonstrating an essential in vivo role for PTCD3 in mtDNA-related functions. Loss-of-function genetic mutant in Drosophila; transcriptomic profiling microPublication biology Medium 38074476
2025 PTCD3 promotes SLC38A2 mRNA stability in colorectal cancer cells in an IGF2BP2-dependent manner, thereby enhancing glutaminolysis and supporting CRC cell proliferation, migration, and invasion. KAT2A-mediated H3K27 acetylation epigenetically upregulates PTCD3 expression. Silencing PTCD3 inhibited CRC tumor growth in vivo. Co-IP, RIP, dual-luciferase assay, siRNA knockdown, xenograft mouse model, ChIP (H3K27ac), CCK-8, scratch and Transwell assays FASEB journal Medium 40304977

Source papers

Stage 0 corpus · 54 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Towards a proteome-scale map of the human protein-protein interaction network. Nature 2090 16189514
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2012 The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts. Molecular cell 973 22681889
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2007 Large-scale mapping of human protein-protein interactions by mass spectrometry. Molecular systems biology 733 17353931
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2018 High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies. Molecular cell 580 29395067
2017 Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science (New York, N.Y.) 533 28302793
2015 A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface. Cell 433 26638075
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2010 Systematic analysis of human protein complexes identifies chromosome segregation proteins. Science (New York, N.Y.) 421 20360068
2015 Ribosome. The structure of the human mitochondrial ribosome. Science (New York, N.Y.) 417 25838379
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
1996 Normalization and subtraction: two approaches to facilitate gene discovery. Genome research 401 8889548
1996 Generation and analysis of 280,000 human expressed sequence tags. Genome research 376 8889549
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2010 Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. Cell 318 21145461
2020 Virus-Host Interactome and Proteomic Survey Reveal Potential Virulence Factors Influencing SARS-CoV-2 Pathogenesis. Med (New York, N.Y.) 291 32838362
2007 Proteomic and functional analysis of Argonaute-containing mRNA-protein complexes in human cells. EMBO reports 283 17932509
2016 The cell proliferation antigen Ki-67 organises heterochromatin. eLife 265 26949251
2017 A Compendium of RNA-Binding Proteins that Regulate MicroRNA Biogenesis. Molecular cell 248 28431233
2021 Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context. Cell metabolism 239 34800366
2011 TEFM (c17orf42) is necessary for transcription of human mtDNA. Nucleic acids research 145 21278163
2020 Discovery of Potent and Selective Epidermal Growth Factor Receptor (EGFR) Bifunctional Small-Molecule Degraders. Journal of medicinal chemistry 143 31895569
2009 Pentatricopeptide repeat domain protein 3 associates with the mitochondrial small ribosomal subunit and regulates translation. FEBS letters 86 19427859
2020 Structural basis of mitochondrial translation. eLife 85 32812867
2013 Identification and characterization of CHCHD1, AURKAIP1, and CRIF1 as new members of the mammalian mitochondrial ribosome. Frontiers in physiology 71 23908630
2016 The mitochondrial translation machinery as a therapeutic target in Myc-driven lymphomas. Oncotarget 58 27635472
2019 Mitochondrial ribosomal protein PTCD3 mutations cause oxidative phosphorylation defects with Leigh syndrome. Neurogenetics 49 30607703
2024 Structural basis of LRPPRC-SLIRP-dependent translation by the mitoribosome. Nature structural & molecular biology 30 39134711
2022 Exploring Degradation of Mutant and Wild-Type Epidermal Growth Factor Receptors Induced by Proteolysis-Targeting Chimeras. Journal of medicinal chemistry 29 35675209
2019 The role of the protein-RNA recognition code in neurodegeneration. Cellular and molecular life sciences : CMLS 21 30980111
2011 Contacts between mammalian mitochondrial translational initiation factor 3 and ribosomal proteins in the small subunit. Biochimica et biophysica acta 19 22015679
2020 Comparative pharmacoproteomics reveals potential targets for berberine, a promising therapy for colorectal cancer. Biochemical and biophysical research communications 15 32087971
2012 Multiple-locus variable-number tandem-repeat analysis of Streptococcus pneumoniae and comparison with multiple loci sequence typing. BMC microbiology 12 23088225
2022 Leigh syndrome is the main clinical characteristic of PTCD3 deficiency. Brain pathology (Zurich, Switzerland) 11 36450274
2020 Genetic determinants of ammonia-induced acute lung injury in mice. American journal of physiology. Lung cellular and molecular physiology 11 33050709
2012 Combining ability analysis for within-boll yield components in upland cotton (Gossypium hirsutum L.). Genetics and molecular research : GMR 6 23007974
2025 Epigenetic Activation of PTCD3 Promotes CRC Glutamine Metabolism and Metastasis via IGF2BP2-Mediated SLC38A2 m6A Modification. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 4 40304977
2022 RNA-sequencing for transcriptional profiling of whole blood in early stage and metastatic pancreatic cancer patients. Cell biology international 3 36229929
2014 First Report of the NA2 Lineage of Phytophthora ramorum from an Ornamental Rhododendron in the Interior of California. Plant disease 2 30708650
2023 A Drosophila melanogaster ortholog of pentatricopeptide repeat domain 3 ( PTCD3 ) is essential for development. microPublication biology 1 38074476
2025 [Clinical and genetic characteristics analysis of 18 children with infantile epileptic spasms syndrome associated with mitochondrial gene variants]. Zhonghua er ke za zhi = Chinese journal of pediatrics 0 40962542
2025 Bioinformatics-based screening and validation of ferroptosis-related genes in sepsis and type 2 diabetes mellitus. Experimental biology and medicine (Maywood, N.J.) 0 41194984
2024 The phenotypic spectrum of PTCD3 deficiency. JIMD reports 0 39544688
2022 Semilunar sign of cornea: A multimodal analysis of the posterior corneal opacity in non-infectious anterior scleritis. Indian journal of ophthalmology 0 35326015