Affinage

MRPL49

Large ribosomal subunit protein mL49 · UniProt Q13405

Round 2 corrected
Length
166 aa
Mass
19.2 kDa
Annotated
2026-04-28
85 papers in source corpus 6 papers cited in narrative 6 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MRPL49 is a structural protein of the human mitochondrial large ribosomal subunit (39S/mt-LSU), where it serves as one of ~48 integral components required for mitoribosomal integrity and mitochondrial translation. Proteomic identification from purified 39S subunits and cryo-EM structures at near-atomic resolution confirm its stable incorporation into the mt-LSU, including in late-stage assembly intermediates (PMID:11551941, PMID:25278503, PMID:28892042). Bi-allelic loss-of-function variants in MRPL49 reduce steady-state levels of both mitoribosomal subunits—particularly the mt-LSU—leading to combined oxidative phosphorylation deficiency (decreased complexes I and IV) and multisystem disease including Perrault syndrome and childhood-onset leukodystrophy (PMID:40043708).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 1996 Medium

    Initial cloning of the NOF gene (later MRPL49) established it as a ubiquitously expressed, evolutionarily conserved 166-amino-acid proline-rich protein at chromosome 11q13, but its molecular function was unknown.

    Evidence cDNA cloning, northern blotting, genomic mapping, and cross-species sequence comparison

    PMID:8786148

    Open questions at the time
    • No functional assignment; protein was not linked to any complex or organelle
    • Single-lab characterization without independent confirmation
  2. 2001 High

    Mass spectrometric identification of MRPL49 as a bona fide subunit of the purified mammalian 39S mitochondrial ribosomal subunit resolved its molecular role, placing it in the mitochondrial translation machinery.

    Evidence Proteolytic digestion of purified bovine 39S mt-LSU followed by LC-MS/MS peptide sequencing

    PMID:11551941

    Open questions at the time
    • Precise position within the mt-LSU structure was unknown
    • Functional consequence of MRPL49 loss had not been tested
  3. 2014 High

    Near-atomic cryo-EM structures of the human mt-LSU provided the first structural context for MRPL49 within the 39S subunit, revealing how mitochondria-specific proteins remodel the ribosomal architecture.

    Evidence Single-particle cryo-EM at 3.4 Å resolution of the human mt-LSU

    PMID:25278503

    Open questions at the time
    • MRPL49-specific protein–protein or protein–rRNA contacts not individually described
    • Role during ribosome assembly versus function was unclear
  4. 2017 High

    Cryo-EM of native late-stage mt-LSU assembly intermediates showed that MRPL49 is already incorporated at these stages, defining its temporal placement in the biogenesis pathway.

    Evidence Single-particle cryo-EM (~3 Å) of natively isolated human mt-LSU assembly intermediates

    PMID:28892042

    Open questions at the time
    • Whether MRPL49 is required for progression through assembly checkpoints was not tested
    • Earliest assembly intermediate in which MRPL49 is incorporated was not determined
  5. 2025 High

    Human genetic and biochemical evidence demonstrated that MRPL49 is essential for mitoribosomal stability and mitochondrial translation: bi-allelic loss-of-function variants cause reduced mt-LSU and mt-SSU levels, combined OXPHOS deficiency (complexes I and IV), and clinically manifest as Perrault syndrome or leukodystrophy.

    Evidence Genome sequencing in nine unrelated families, complexome profiling and OXPHOS quantification in patient fibroblasts

    PMID:40043708

    Open questions at the time
    • Whether the mt-SSU reduction is a secondary consequence of mt-LSU instability or an independent effect is unresolved
    • No rescue experiment (complementation with wild-type MRPL49) was reported
    • Mechanism by which specific OXPHOS complexes (I and IV but not others) are preferentially affected is not explained

Open questions

Synthesis pass · forward-looking unresolved questions
  • The precise molecular contacts of MRPL49 within the mt-LSU, its contributions to specific ribosome assembly steps, and the basis for tissue-selective disease manifestations remain uncharacterized.
  • No high-resolution map of MRPL49-specific rRNA or protein contacts
  • No conditional knockout or depletion model to dissect assembly versus translation functions
  • Genotype-phenotype correlation (Perrault syndrome vs. leukodystrophy) not mechanistically explained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3
Localization
GO:0005739 mitochondrion 4 GO:0005840 ribosome 3
Pathway
R-HSA-392499 Metabolism of proteins 3 R-HSA-1852241 Organelle biogenesis and maintenance 1
Complex memberships
39S mitochondrial ribosomal large subunit (mt-LSU)

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 The human NOF gene (later identified as MRPL49), located at chromosome 11q13 immediately adjacent to FAU in a head-to-head configuration, encodes a conserved protein of 166 amino acids that is proline-rich. Its mRNA (~2.2 kb) is ubiquitously expressed, and the protein shows >80% identity to mouse and rat orthologs. The gene spans ~5 kb with 4 exons/3 introns and is not disrupted by a t(11;17)(q13;q21) translocation associated with B-non-Hodgkin lymphoma. cDNA cloning, genomic Southern blotting, northern blotting, chromosomal mapping, sequence analysis Genomics Medium 8786148
2001 MRPL49 (MRP-L49) was identified as one of 48 distinct proteins comprising the large subunit (39S) of the mammalian mitochondrial ribosome. It was identified by proteolytic digestion of whole 39S subunits followed by LC-MS/MS peptide sequencing and EST database searching, establishing it as a bona fide structural component of the mt-LSU. Proteolytic digestion of purified 39S subunits, liquid chromatography–mass spectrometry (LC-MS/MS), EST database searching The Journal of biological chemistry High 11551941
2014 Cryo-EM structure of the human mitochondrial large ribosomal subunit (mt-LSU) at 3.4 Å resolution revealed MRPL49 as one of 48 proteins in the 39S subunit, including 21 mitochondria-specific proteins. The structure showed extensive remodeling of the central protuberance and adaptations of the exit tunnel for hydrophobic nascent peptides, providing the structural context for MRPL49's role as an integral mt-LSU component. Single-particle cryo-electron microscopy (cryo-EM) at 3.4 Å resolution Science High 25278503
2017 Cryo-EM structures of two late-stage assembly intermediates of the human mt-LSU (~3 Å resolution) isolated from native cell pools revealed the timing of rRNA folding and protein incorporation during mitoribosomal maturation. MRPL49 is present as an integral structural component of the mt-LSU in these assembly states, and comparison of intermediates provided insight into the sequential steps of large subunit biogenesis. Single-particle cryo-EM (~3 Å), native isolation of assembly intermediates from human cell line Nature structural & molecular biology High 28892042
2020 BioID proximity-labeling using 100 mitochondrial baits in human cells placed MRPL49 within the high-confidence mitochondrial proximity interaction network, consistent with its localization to the mitochondrial matrix as part of the large mitoribosomal subunit. MRPL49 was detected as a proximity interactor of other mt-LSU proteins, supporting its stable integration into the 39S subunit in the mitochondrial compartment. BioID proximity-dependent biotinylation with 100 mitochondrial baits, mass spectrometry Cell metabolism Medium 32877691
2025 Bi-allelic loss-of-function variants in MRPL49 cause combined oxidative phosphorylation deficiency (COXPD). Complexome profiling of patient fibroblasts demonstrated reduced steady-state levels of both small and large mitochondrial ribosomal subunits (with a more pronounced reduction of the mt-LSU), without evidence of altered mitoribosomal assembly intermediates. This ribosomal insufficiency results in reduced levels of OXPHOS complexes I and IV, consistent with impaired mitochondrial translation. Clinical presentations ranged from Perrault syndrome (sensorineural hearing loss + primary ovarian insufficiency) to severe childhood-onset leukodystrophy, microcephaly, and retinal dystrophy. Genome sequencing, complexome profiling of patient fibroblasts, OXPHOS enzyme complex quantification, clinical phenotyping of nine unrelated families American journal of human genetics High 40043708

Source papers

Stage 0 corpus · 85 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
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
2009 A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. Cell 843 19490893
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
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
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2010 Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. Cell 318 21145461
2014 Structure of the large ribosomal subunit from human mitochondria. Science (New York, N.Y.) 262 25278503
2021 Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context. Cell metabolism 239 34800366
2016 Structure and Function of the Mitochondrial Ribosome. Annual review of biochemistry 217 27023846
2001 The large subunit of the mammalian mitochondrial ribosome. Analysis of the complement of ribosomal proteins present. The Journal of biological chemistry 216 11551941
2018 An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations. Nature communications 201 29568061
2019 A protein-interaction network of interferon-stimulated genes extends the innate immune system landscape. Nature immunology 159 30833792
2010 A functional peptidyl-tRNA hydrolase, ICT1, has been recruited into the human mitochondrial ribosome. The EMBO journal 153 20186120
2015 BioID-based Identification of Skp Cullin F-box (SCF)β-TrCP1/2 E3 Ligase Substrates. Molecular & cellular proteomics : MCP 149 25900982
2020 A High-Density Human Mitochondrial Proximity Interaction Network. Cell metabolism 148 32877691
2019 Mapping the proximity interaction network of the Rho-family GTPases reveals signalling pathways and regulatory mechanisms. Nature cell biology 137 31871319
2017 Structures of the human mitochondrial ribosome in native states of assembly. Nature structural & molecular biology 136 28892042
2016 SPATA2 Links CYLD to LUBAC, Activates CYLD, and Controls LUBAC Signaling. Molecular cell 134 27591049
2013 A newly uncovered group of distantly related lysine methyltransferases preferentially interact with molecular chaperones to regulate their activity. PLoS genetics 131 23349634
2011 Interactions of pathological hallmark proteins: tubulin polymerization promoting protein/p25, beta-amyloid, and alpha-synuclein. The Journal of biological chemistry 131 21832049
2022 Human transcription factor protein interaction networks. Nature communications 123 35140242
2015 KAP1 Recruitment of the 7SK snRNP Complex to Promoters Enables Transcription Elongation by RNA Polymerase II. Molecular cell 113 26725010
2021 Systematically defining selective autophagy receptor-specific cargo using autophagosome content profiling. Molecular cell 105 33545068
2014 N-of-1 (single-patient) trials for statin-related myalgia. Annals of internal medicine 92 24737272
2003 Light stimulates a transducin-independent increase of cytoplasmic Ca2+ and suppression of current in cones from the zebrafish mutant nof. The Journal of neuroscience : the official journal of the Society for Neuroscience 82 12533607
2021 Molecular profiling of advanced malignancies guides first-line N-of-1 treatments in the I-PREDICT treatment-naïve study. Genome medicine 76 34607609
2007 Identification of a zebrafish cone photoreceptor-specific promoter and genetic rescue of achromatopsia in the nof mutant. Investigative ophthalmology & visual science 72 17251445
2015 PCSK9 inhibitors and neurocognitive adverse events: exploring the FDA directive and a proposal for N-of-1 trials. Drug safety 56 25989944
2022 Consensus Guidelines for the Design and In Vitro Preclinical Efficacy Testing N-of-1 Exon Skipping Antisense Oligonucleotides. Nucleic acid therapeutics 40 36516128
1991 Purification and characterization of an 82-kD membrane protein as a neurite outgrowth factor binding protein: possible involvement of NOF binding protein in axonal outgrowth in developing retina. The Journal of cell biology 35 1988463
2010 NOF1 encodes an Arabidopsis protein involved in the control of rRNA expression. PloS one 34 20877469
2005 A pilot study of ondansetron plus metopimazine vs. ondansetron monotherapy in children receiving highly emetogenic chemotherapy: a Bayesian randomized serial N-of-1 trials design. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer 29 16052316
2024 The state-of-the-art of N-of-1 therapies and the IRDiRC N-of-1 development roadmap. Nature reviews. Drug discovery 23 39496921
2012 Simvastatin decreases levodopa-induced dyskinesia in monkeys, but not in a randomized, placebo-controlled, multiple cross-over ("n-of-1") exploratory trial of simvastatin against levodopa-induced dyskinesia in Parkinson's disease patients. Parkinsonism & related disorders 23 23283428
2021 Individual Postprandial Glycemic Responses to Diet in n-of-1 Trials: Westlake N-of-1 Trials for Macronutrient Intake (WE-MACNUTR). The Journal of nutrition 21 34255080
2024 A framework for N-of-1 trials of individualized gene-targeted therapies for genetic diseases. Nature communications 19 39532857
2017 Capturing the systemic immune signature of a norovirus infection: an n-of-1 case study within a clinical trial. Wellcome open research 19 28815218
1990 Characterization of the FB-NOF transposable element of Drosophila melanogaster. Genetics 18 2174013
2017 Lamin A expression in circulating osteoprogenitors as a potential biomarker for frailty: The Nepean Osteoporosis and Frailty (NOF) Study. Experimental gerontology 17 29203402
2024 Tumor-agnostic baskets to N-of-1 platform trials and real-world data: Transforming precision oncology clinical trial design. Cancer treatment reviews 14 38484408
2012 Discovery-based nutritional systems biology: developing N-of-1 nutrigenomic research. International journal for vitamin and nutrition research. Internationale Zeitschrift fur Vitamin- und Ernahrungsforschung. Journal international de vitaminologie et de nutrition 14 23798052
2022 Genomic landscape of lymphatic malformations: a case series and response to the PI3Kα inhibitor alpelisib in an N-of-1 clinical trial. eLife 13 35787784
2021 The effect of a color tattoo on the local skin redox regulatory network: an N-of-1 study. Free radical research 10 33855906
2016 Efficacy of ultra-micronized palmitoylethanolamide (um-PEA) in geriatric patients with chronic pain: study protocol for a series of N-of-1 randomized trials. Trials 10 27473188
2020 Ataluren/ivacaftor combination therapy: Two N-of-1 trials in cystic fibrosis patients with nonsense mutations. Pediatric pulmonology 9 32281737
2015 OncoRep: an n-of-1 reporting tool to support genome-guided treatment for breast cancer patients using RNA-sequencing. BMC medical genomics 9 25989980
2016 Comparative effectiveness of antihypertensive treatment for older children with primary hypertension: study protocol for a series of n-of-1 randomized trials. Trials 8 26746195
2017 Testing for differentially expressed genetic pathways with single-subject N-of-1 data in the presence of inter-gene correlation. Statistical methods in medical research 7 28552011
2024 N-of-1 medicine. Singapore medical journal 6 38527301
2016 Evaluating the Utility of a 'N-of-1' Precision Cancer Medicine Strategy: The Case for 'Time-to-Subsequent-Disease Progression'. Oncology 5 27705967
2013 FB-NOF is a non-autonomous transposable element, expressed in Drosophila melanogaster and present only in the melanogaster group. Gene 5 23685284
1996 Isolation, cDNA, and genomic structure of a conserved gene (NOF) at chromosome 11q13 next to FAU and oriented in the opposite transcriptional orientation. Genomics 5 8786148
2025 Toward an Extensible Regulatory Framework for N-of-1 to N-of-Few Personalized RNA Therapy Design. Therapeutic innovation & regulatory science 4 40014258
2025 Bi-allelic variants in MRPL49 cause variable clinical presentations, including sensorineural hearing loss, leukodystrophy, and ovarian insufficiency. American journal of human genetics 4 40043708
2025 Blueprint for clinical N-of-1 strategies with off-label precision treatments in monogenic epilepsies. Orphanet journal of rare diseases 4 40524218
2023 Effectiveness of L-serine supplementation in children with a GRIN2B loss-of-function mutation: Rationale and protocol for single patient (n-of-1) multiple cross-over trials. Contemporary clinical trials communications 3 38144875
2018 A Pilot Study of Amino Acids in Unresectable Non-Small-Cell Lung Cancer Patients During Chemotherapy: A Randomized Serial N-of-1 Trials Design. Nutrition and cancer 3 30451538
2005 An FB-NOF mediated duplication of the white gene is responsible for the zeste1 phenotype in some Drosophila melanogaster unstable strains. Molecular genetics and genomics : MGG 3 16333669
2025 Efficacy and Safety of Photobiomodulation in MELAS: Protocol for a Series of N-of-1 Trials. Journal of clinical medicine 2 40142856
2025 Hypoxic conditioning in Parkinson's disease: randomized controlled multiple N-of-1 trials. Nature communications 2 41006236
2024 Rethinking the transfusion pathway in myelodysplastic syndromes: Study protocol for a novel randomized feasibility n-of-1 trial of weekly-interval red cell transfusion in myelodysplastic syndromes. Transfusion 2 38214417
2024 N-of-1 health optimization: Digital monitoring of biomarker dynamics to gamify adherence to metabolic switching. PNAS nexus 2 38881838
2023 Complete and sustained remission of hypercortisolism with pasireotide treatment of an adrenocorticotropic hormone (ACTH)-secreting thoracic neuroendocrine tumor: an n-of-1 trial. Endocrine journal 2 36697023
2023 The importance of personalization in high altitude protocols for hematologic and metabolic benefits in sports: A multi-dimensional N-of-1 case study. Heliyon 2 38170057
2021 Results of a 5-Year N-of-1 Growth Hormone Releasing Hormone Gene Therapy Experiment. Rejuvenation research 2 34841890
2024 Biallelic variants in MRPL49 cause variable clinical presentations, including sensorineural hearing loss, leukodystrophy, and ovarian insufficiency. medRxiv : the preprint server for health sciences 1 39417135
2026 Matching hallmarks of cancer complexity with N-of-1 precision oncology. Med (New York, N.Y.) 0 41831434
2026 From Genomic Diagnosis to Personalized RNA Medicine: Advances in Next-Generation Sequencing and N-of-1 Antisense Oligonucleotide Therapies for Rare Genetic Diseases. Genes 0 41898852
2026 An n-of-1 gene-directed drug repurposing trial for an ultrarare genetic condition. Epilepsia 0 41999155
2026 From N-of-1 to versatility in propionic acidemia: Antisense oligonucleotide-mediated skipping of a constitutive PCCA pseudoexon. Molecular therapy. Nucleic acids 0 42028575
2025 Athlete burnout and biomarkers: An exploratory, longitudinal N-of-1 study. Psychology of sport and exercise 0 40374022
2025 Personalized N-of-1 Combination Therapies for Advanced Gastrointestinal Stromal Tumors. JCO precision oncology 0 40700673
2025 Milasen: The Emerging Era of Patient-Customized N-of-1 Antisense Oligonucleotides as Therapeutic Agents for Genetic Diseases. Methods in molecular biology (Clifton, N.J.) 0 40720011
2025 Rethinking p16, p53, and HPV in HNCSCC through lessons from glioblastoma subclonal evolution toward patient-centric N-of-1 single-cell RNA sequencing paradigm. World journal of clinical cases 0 41256339
2025 Potential benefits of l-serine in children with GRIN2B loss-of-function variants: Randomized n-of-1 trials. Molecular genetics and metabolism 0 41265180
2024 Corrigendum to "Effectiveness of L-serine supplementation in children with a GRIN2B loss-of-function mutation: Rationale and protocol for single patient (n-of-1) multiple cross-over trials" [Contemp. Clin. Trials Commun. 36 (2023)/ DOI: 10.1016/j.conctc.2023.101233]. Contemporary clinical trials communications 0 38533474
2023 [Cystic fibrosis - ETI and type 2 N-of-1 trials : the next step]. Revue medicale de Liege 0 37830320
1990 Possible involvement of neurite outgrowth factor (NOF) receptor in axonal outgrowth from developing chick retina. Neuroscience research. Supplement : the official journal of the Japan Neuroscience Society 0 1701872