Affinage

RPL21

Large ribosomal subunit protein eL21 · UniProt P46778

Length
160 aa
Mass
18.6 kDa
Annotated
2026-06-10
32 papers in source corpus 12 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/6 claims corpus-supported (67%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RPL21 (eL21) is a structural protein of the large ribosomal subunit that makes direct contact with large-subunit rRNA, a contact established in the bacterial L21 ortholog by cross-linking to 23S RNA within the 50S subunit (PMID:6170935). The protein is highly conserved across bacteria, fungi, and mammals, with the eukaryotic forms (~159 residues in rat) substantially larger than the 103-residue E. coli protein (PMID:387076, PMID:2751657, PMID:8428379). Like other ribosomal protein genes, RPL21 expression is controlled post-transcriptionally: in Entamoeba histolytica, the two gene copies are transcribed equally but differ in polyribosome association, with 5' flanking regions—not 3'—dictating differential translational efficiency (PMID:9515695). In humans, a missense mutation (p.Arg32Gln) causes autosomal dominant hereditary hypotrichosis simplex, establishing a requirement for RPL21 in hair follicle development (PMID:21412954). Beyond its ribosomal role, RPL21 carries out extra-ribosomal functions in cancer: it sustains DNA replication through MCM2-7 and drives G1-S progression by regulating E2F1, CCND1, and CCNE1, such that its loss induces G1 arrest and caspase-8-dependent mitochondrial apoptosis (PMID:33014855). It also directly binds LAMP3—an interaction that reciprocally stabilizes RPL21 against ubiquitin-proteasome degradation while RPL21 activates TFEB to upregulate LAMP3—to promote FAK/paxillin/ERK-mediated focal adhesion formation and tumor invasion (PMID:37062845).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 1981 Medium

    Established that L21 is a bona fide rRNA-contacting structural component of the large ribosomal subunit rather than a peripheral factor, by localizing its direct binding site on rRNA.

    Evidence 2-iminothiolane RNA-protein cross-linking and RNA sequencing in the E. coli 50S subunit

    PMID:6170935

    Open questions at the time
    • No mutagenesis validation of the contact site
    • Bacterial system; eukaryotic eL21 rRNA contacts not directly mapped here
  2. 1979 High

    Defined the primary structure and genomic organization of L21, fixing its identity as a small basic ribosomal protein encoded in a conserved operon with L27.

    Evidence Edman degradation primary sequencing and P1 transduction mapping in E. coli

    PMID:378941 PMID:387076

    Open questions at the time
    • Structure determined for bacterial protein only
    • Functional role in assembly not addressed
  3. 1989 Medium

    Extended L21 conservation to mammals, showing the eukaryotic protein is larger and multicopy in the genome, framing it as a conserved eukaryotic ribosomal protein.

    Evidence cDNA and N-terminal protein sequencing plus Southern blot in rat

    PMID:2751657

    Open questions at the time
    • Which copies are expressed vs pseudogenes not resolved
    • No functional characterization
  4. 1998 High

    Showed that L21 abundance is set post-transcriptionally at the level of translation, identifying the 5' flanking region as the controlling element—addressing how ribosomal protein output is tuned.

    Evidence Polyribosome fractionation and CAT reporter assays with deletion constructs in E. histolytica

    PMID:9515695

    Open questions at the time
    • Trans-acting factors binding the 5' region unidentified
    • Whether mammalian RPL21 uses the same mechanism unknown
  5. 2011 Medium

    Linked RPL21 to a human Mendelian phenotype, demonstrating that a specific missense allele impairs hair follicle development and that ribosomal protein dosage/function matters in a tissue-specific manner.

    Evidence Exome sequencing and co-segregation in two hypotrichosis families with control exclusion

    PMID:21412954

    Open questions at the time
    • No functional rescue or mechanistic explanation for tissue specificity
    • How Arg32Gln alters protein function not determined
  6. 2020 Medium

    Revealed an extra-ribosomal proliferative role, showing RPL21 supports DNA replication and G1-S transit through MCM2-7 and E2F1/cyclin regulation, with loss triggering apoptosis.

    Evidence siRNA knockdown, transcriptomics, luciferase, cell cycle/apoptosis assays and xenografts in pancreatic cancer cells

    PMID:33014855

    Open questions at the time
    • Whether effects are direct or secondary to impaired ribosome function unresolved
    • Single-lab findings
    • Mechanism of E2F1 regulation not defined
  7. 2023 Medium

    Identified a direct protein partner, mapping the RPL21-LAMP3 interaction and a reciprocal stabilization/transcriptional circuit driving focal adhesion signaling and invasion.

    Evidence GST/His pull-down with domain deletions, co-IP, TFEB reporter, and invasion/metastasis assays in colorectal cancer

    PMID:37062845

    Open questions at the time
    • E3 ligase mediating RPL21 ubiquitination unidentified
    • Single-lab findings
    • Relationship to ribosomal pool of RPL21 unclear
  8. 2025 Medium

    Reported a surprising cell-surface pool of eL21 lacking canonical secretion signals that is functionally targetable by antibodies, expanding the possible extra-ribosomal localization.

    Evidence Complementary localization assays and anti-eL21 antibody functional assays in triple-negative breast cancer cells (preprint)

    Open questions at the time
    • Mechanism of externalization unknown
    • Preprint, not peer-reviewed
    • Surface receptor/binding partner unidentified

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the conserved ribosomal RPL21 acquires and executes its distinct extra-ribosomal activities—DNA replication control, LAMP3-driven invasion, and cell-surface display—and how these relate to its translational function remains unresolved.
  • No unifying mechanism connecting ribosomal and extra-ribosomal roles
  • No structural model of human eL21 in its non-ribosomal complexes
  • Functional consequence of the ATXN2 interaction uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 2 GO:0003723 RNA binding 1
Localization
GO:0005840 ribosome 2
Pathway
R-HSA-392499 Metabolism of proteins 2
Partners
ATXN2LAMP3
Complex memberships
60S/50S large ribosomal subunit

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1981 E. coli ribosomal protein L21 is cross-linked to 23S RNA at positions 540-548, establishing direct RNA-protein contact within the 50S subunit at this specific site. 2-iminothiolane RNA-protein cross-linking followed by UV irradiation and RNA sequencing Nucleic acids research Medium 6170935
1979 The E. coli genes rplU (encoding L21) and rpmA (encoding L27) form a gene cluster located at 68.1 min on the chromosome, between argG and gltB, establishing their genomic organization as a co-regulated unit. P1kc-mediated transduction mapping using structural gene mutants Journal of bacteriology Medium 378941
1979 E. coli ribosomal protein L21 consists of a single polypeptide chain of 103 amino acids with a molecular weight of 11,565 Da; its primary structure was fully determined. Protein sequencing by Edman degradation of tryptic, protease, and cyanogen bromide fragments; liquid-phase sequenator Biochemistry High 387076
1989 Rat ribosomal protein L21 consists of 159 amino acids (MW 18,322 Da) with the N-terminal methionine removed post-translationally; the gene exists in 16-23 copies in the nuclear genome. cDNA sequencing and NH2-terminal protein sequencing; Southern blot hybridization Biochemical and biophysical research communications Medium 2751657
1993 The E. coli rplU (L21) and rpmA (L27) genes compose an operon at coordinates 3,351.7–3,352.3 kb on the physical map, with an upstream ORF in the opposite orientation encoding a prenyltransferase-related protein. Genomic cloning, nucleotide sequencing, and ordered clone bank analysis DNA sequence : the journal of DNA sequencing and mapping Medium 8312607
1993 Saccharomyces cerevisiae URP1 (yeast L21 homolog) is a single-copy gene expressed in vivo, interrupted by a 5' intron and preceded by upstream regulatory elements typical of ribosomal protein genes, and encodes a ~18,200 Da protein with 59% sequence identity to rat L21. Molecular cloning, DNA sequencing, Northern blot analysis Current genetics Medium 8428379
1998 Expression of Entamoeba histolytica ribosomal protein L21 is regulated at the post-transcriptional level: both rp-L21 gene copies are transcribed at similar levels but differ in their relative association with polyribosomes, and the 5' flanking regions (not 3') determine differential translational efficiency. Polyribosome fractionation, Northern/slot blot hybridization, CAT reporter gene assay with stable transfection into E. histolytica and E. dispar Molecular microbiology High 9515695
1980 The cyR1 gene of Podospora anserina is the structural gene for ribosomal protein L21; mutation of cyR1 alters L21 and confers cycloheximide resistance, and revertant analysis confirmed L21 as the direct target. Isolation and analysis of revertants from cycloheximide-resistant mutant; ribosomal protein gel analysis Molecular & general genetics Medium 6934365
2011 A missense mutation c.95G>A (p.Arg32Gln) in human RPL21 causes autosomal dominant hereditary hypotrichosis simplex, demonstrating that RPL21 function is required for normal hair follicle development. Locus mapping, exome sequencing, co-segregation analysis in two unrelated Chinese families, exclusion from 200 normal controls and databases Human mutation Medium 21412954
2016 In E. coli, obgE (encoding the essential Obg GTPase involved in ribosome assembly) is co-transcribed with ribosomal protein genes rplU (L21) and rpmA in an operon; ~75% of transcripts terminate before obgE due to a transcriptional terminator between rpmA and yhbE; operon expression is highest during exponential growth and is derepressed in ppGpp/DksA mutants via a post-transcription-initiation mechanism. Transcriptional analysis, identification of terminator, growth-phase expression profiling, in vitro transcription assays with ppGpp and DksA Journal of bacteriology High 27137500
2020 RPL21 knockdown in pancreatic cancer cells inhibits DNA replication by reducing MCM2-7 expression, induces G1 cell cycle arrest via downregulation of CCND1 and CCNE1, and triggers caspase-8-dependent mitochondrial apoptosis; RPL21 controls G1-S progression through regulation of E2F1 transcription factor activity. siRNA knockdown, flow cytometry, transcriptome sequencing, luciferase reporter assay, mitochondrial membrane potential assay, caspase activity assay, xenograft mouse model Frontiers in oncology Medium 33014855
2023 RPL21 directly binds to LAMP3 via its aa 1-40 and aa 111-160 segments interacting with aa 341-416 of LAMP3; this interaction stabilizes RPL21 protein by suppressing ubiquitin-proteasome-mediated degradation; RPL21 also activates TFEB transcription factor to upregulate LAMP3 expression; together RPL21 and LAMP3 promote focal adhesion formation via FAK/paxillin/ERK signaling to drive CRC invasion and metastasis. GST/His pull-down assay, co-immunoprecipitation, transcriptome sequencing, dual-luciferase reporter assay, immunofluorescence, wound healing/transwell assays, orthotopic mouse model, cell adhesion assay Cellular & molecular biology letters Medium 37062845
2025 RPL21 (eL21) is present in an extracellular/cell-surface form on triple negative breast cancer cells despite lacking transmembrane domains or secretion signals; anti-eL21 antibodies induce cell cycle arrest and apoptosis, indicating an extra-ribosomal function at the cancer cell surface. Multiple complementary localization approaches with broad antibody panel; anti-eL21 antibody functional assays measuring proliferation, cell cycle, and apoptosis bioRxivpreprint Medium
2024 RPL21 shows increased binding to ATXN2 in a polyglutamine-expansion mouse model (co-immunoprecipitation in cerebellum), suggesting RPL21 participates in the ATXN2 SH3-domain interactome, though the functional consequence of this interaction remains uncharacterized. Co-immunoprecipitation profiling in mouse cerebellum bioRxivpreprint Low

Source papers

Stage 0 corpus · 32 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1981 The use of 2-iminothiolane as an RNA-protein cross-linking agent in Escherichia coli ribosomes, and the localisation on 23S RNA of sites cross-linked to proteins L4, L6, L21, L23, L27 and L29. Nucleic acids research 72 6170935
1976 Isolation of eukaryotic ribosomal proteins. Purification and characterization of the 60 S ribosomal subunit proteins L4, L5, L7, L9, L11, L12, L13, L21, L22, L23, L26, L27, L30, L33, L35', L37, and L39. The Journal of biological chemistry 70 1002715
1995 Cloning, sequencing and expression of the L5, L21, L27a, L28, S5, S9, S10 and S29 human ribosomal protein mRNAs. Biochimica et biophysica acta 66 7772601
2011 Mutation in ribosomal protein L21 underlies hereditary hypotrichosis simplex. Human mutation 56 21412954
2023 RPL21 interacts with LAMP3 to promote colorectal cancer invasion and metastasis by regulating focal adhesion formation. Cellular & molecular biology letters 33 37062845
2003 Multiple monovalent ion-dependent pathways for the folding of the L-21 Tetrahymena thermophila ribozyme. Journal of molecular biology 32 12691754
2013 Cytokine expression in head-kidney leucocytes of European sea bass (Dicentrarchus labrax L.) after incubation with the probiotic Vagococcus fluvialis L-21. Fish & shellfish immunology 25 23927874
2020 RPL21 siRNA Blocks Proliferation in Pancreatic Cancer Cells by Inhibiting DNA Replication and Inducing G1 Arrest and Apoptosis. Frontiers in oncology 22 33014855
1979 Genes coding for ribosomal proteins S15, L21, and L27 map near argG in Escherichia coli. Journal of bacteriology 22 378941
1993 RIM2, MSI1 and PGI1 are located within an 8 kb segment of Saccharomyces cerevisiae chromosome II, which also contains the putative ribosomal gene L21 and a new putative essential gene with a leucine zipper motif. Yeast (Chichester, England) 21 8346681
1994 Phorbol ester induction of differentiation and apoptosis in the K562 cell line is accompanied by marked decreases in the stability of globin mRNAs and decreases in the steady state level of mRNAs encoding for ribosomal proteins L35, L31, L27, and L21. Cellular & molecular biology research 20 7804323
2014 The in vitro immunomodulatory effect of extracellular products (ECPs) of Vagococcus fluvialis L21 on European sea bass (Dicentrarchus labrax) leucocytes. Fish & shellfish immunology 19 25485483
2009 In situ expression of ribosomal protein L21 in developing tooth germ of the mouse lower first molar. Journal of molecular histology 17 20043235
1991 Structure and evolution of the Tetrahymena thermophila gene encoding ribosomal protein L21. Gene 16 2016059
1998 Regulation of expression of ribosomal protein L-21 genes of Entamoeba histolytica and E. dispar is at the post-transcriptional level. Molecular microbiology 14 9515695
1979 Amino acid sequence of the ribosomal protein L21 of Escherichia coli. Biochemistry 14 387076
1992 A 16 kb small single-copy region separates the plastid DNA inverted repeat of the unicellular red alga Cyanidium caldarium: physical mapping of the IR-flanking regions and nucleotide sequences of the psbD-psbC, rps16, 5S rRNA and rpl21 genes. Plant molecular biology 13 1511125
2003 Architecture and transcriptional activity of the initiator element of the TATA-less RPL21 gene. The Plant journal : for cell and molecular biology 11 12969427
1994 Characterization of two distinct gene transcripts for ribosomal protein L21 from pathogenic and nonpathogenic strains of Entamoeba histolytica. Gene 11 7959049
1989 The primary structure of rat ribosomal protein L21. Biochemical and biophysical research communications 11 2751657
2025 Lacticaseibacillus paracasei L21 and Its Postbiotics Ameliorate Ulcerative Colitis Through Gut Microbiota Modulation, Intestinal Barrier Restoration, and HIF1α/AhR-IL-22 Axis Activation: Combined In Vitro and In Vivo Evidence. Nutrients 10 40806121
1997 S2F, a leaf-specific trans-acting factor, binds to a novel cis-acting element and differentially activates the RPL21 gene. The Plant cell 10 9286115
1993 Cloning and nucleotide sequencing of the genes, rpIU and rpmA, for ribosomal proteins L21 and L27 of Escherichia coli. DNA sequence : the journal of DNA sequencing and mapping 10 8312607
1980 A new mutant form of the ribosomal protein L21 in the fungus Podospora anserina: identification of the structural gene for this protein. Molecular & general genetics : MGG 8 6934365
2024 Efficient nitrogen removal by heterotrophic nitrification-aerobic denitrification yeast Candida boidinii L21: Performance, pathway and application. Bioresource technology 7 39393649
2017 Molecular cloning and characterization of porcine ribosomal protein L21. Journal of veterinary science 7 28057907
2016 Coexpression of Escherichia coli obgE, Encoding the Evolutionarily Conserved Obg GTPase, with Ribosomal Proteins L21 and L27. Journal of bacteriology 6 27137500
2007 Specificity of cyanine dye L-21 aggregation in solutions with nucleic acids. Journal of fluorescence 6 17564820
2014 Wheat-specific gene, ribosomal protein l21, used as the endogenous reference gene for qualitative and real-time quantitative polymerase chain reaction detection of transgenes. Journal of agricultural and food chemistry 5 25325387
1993 Yeast single copy gene URP1 is a homolog of rat ribosomal protein gene L21. Current genetics 4 8428379
2023 Capped L21-norm-based common spatial patterns for EEG signals classification applicable to BCI systems. Medical & biological engineering & computing 1 36658415
1992 Chromosome walk in Entamoeba histolytica: the gene encoding for ribosomal protein L21 neighbors one of the actin genes. Archives of medical research 0 1340321

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