{"gene":"RPS18","run_date":"2026-06-10T07:46:27","timeline":{"discoveries":[{"year":2000,"finding":"Crystal structure of the S15-S6-S18-rRNA complex from Thermus thermophilus 30S subunit central domain revealed that S15 binds rRNA first, inducing a conformational reorganization of two three-helix junctions that creates the RNA fold necessary for subsequent cooperative binding of S6 and S18.","method":"X-ray crystallography at 2.6 Å resolution","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with atomic resolution, directly demonstrates assembly mechanism and protein-RNA contacts","pmids":["10753109"],"is_preprint":false},{"year":1988,"finding":"Chemical probing of 16S rRNA in reconstituted complexes showed that S6 and S18 binding is cooperative and dependent on prior binding of S15; S6, S18, and S11 interact with the 690-720 and 790 loop regions of 16S rRNA near P-site nucleotides.","method":"Chemical probing of rRNA with structure-specific probes in reconstituted protein-rRNA complexes","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal chemical and enzymatic probes, replicated across two independent studies (PMID 2459389 and 3373530)","pmids":["2459389","3373530"],"is_preprint":false},{"year":1984,"finding":"Cooperative assembly of S6, S8, S15, and S18 with 16S rRNA was dissected: S8 and S15 bind independently; S18 binding requires S8 and S15; S6 binding requires S8, S15, and S18. Together they protect the entire central domain (nucleotides 560–890) of 16S rRNA.","method":"Binding dependency assays and RNase protection of reconstituted ribonucleoprotein complexes; gel electrophoresis and centrifugation fractionation","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (protein binding dependency, RNP fragment analysis, RNA footprinting), replicated in subsequent studies","pmids":["6208366"],"is_preprint":false},{"year":2001,"finding":"S6 and S18 form a stable heterodimer in solution (Kd ~8.7 nM) that binds cooperatively to the S15-rRNA complex (Kd ~2.7 nM). Presence of S15 increases S6:S18 affinity for RNA by at least four orders of magnitude. S6 or S18 alone do not bind rRNA.","method":"Isothermal titration calorimetry and gel mobility shift assays with Aquifex aeolicus proteins","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — quantitative thermodynamic measurements with two orthogonal methods (ITC and gel shift), single lab","pmids":["11601845"],"is_preprint":false},{"year":1987,"finding":"The rimI gene of E. coli encodes an N-terminal acetyltransferase that specifically acetylates the N-terminal alanine of ribosomal protein S18; mutation in rimI abolishes S18 acetylation without affecting S5 or L12 acetylation.","method":"Gene cloning, insertional mutagenesis, N-terminal amino acid sequence analysis of wild-type and mutant S18","journal":"Molecular & general genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct enzymatic identification with sequence-level confirmation, replicated across two papers (PMID 2828880 and 6991870)","pmids":["2828880","6991870"],"is_preprint":false},{"year":2008,"finding":"Crystal structure of RimI from Salmonella typhimurium in complex with CoA, AcCoA, and a bisubstrate inhibitor (CoA-S-acetyl-ARYFRR) reveals a direct nucleophilic addition-elimination mechanism for N-alpha-acetylation of S18, with Glu103 as the catalytic base and Tyr115 as the catalytic acid.","method":"X-ray crystallography of RimI complexes; steady-state kinetics with S18 peptide substrate","journal":"Protein science","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with substrate analog plus kinetic characterization, direct mechanism elucidation","pmids":["18596200"],"is_preprint":false},{"year":1978,"finding":"Affinity labeling with a chemically reactive AUG analog cross-linked exclusively to protein S18 at cysteine-10, inhibiting fMet-tRNA binding to the P-site and stimulating elongation-factor-dependent Met-tRNA binding; implicating S18 cysteine-10 as part of the mRNA-binding site near the aminoacyl-tRNA binding site of E. coli ribosomes.","method":"Affinity cross-linking with bromoacetamidophenyl-AUG analog; peptide and amino acid analysis","journal":"European journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct chemical cross-linking with site identification, but single lab and single method","pmids":["365533"],"is_preprint":false},{"year":1979,"finding":"Fluorescent labeling of E. coli 30S ribosomes with IAEDANS attached specifically to cysteine-10 of S18; the labeled ribosomes are fully active, and fluorescence quenching upon mRNA binding provides a direct assay for mRNA-ribosome interaction.","method":"Fluorescent dye conjugation, competitive N-ethylmaleimide labeling, mRNA binding fluorescence assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization of labeling site with functional validation, single lab","pmids":["376533"],"is_preprint":false},{"year":1988,"finding":"RNA-protein cross-linking with trans-diamminedichloroplatinum(II) in E. coli 30S subunits identified three cross-linking sites for S18 on 16S rRNA: a major site at region 825-858, and two minor sites at regions 434-500 and 233-297.","method":"Reversible RNA-protein cross-linking followed by nuclease digestion and protein identification","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct cross-linking with site mapping, consistent with other structural data, single lab","pmids":["2449359"],"is_preprint":false},{"year":1987,"finding":"RNA-protein cross-linking in E. coli 30S subunits placed the S18 cross-link site at positions 845-851 of 16S rRNA.","method":"Chemical cross-linking with bis-(2-chloroethyl)-methylamine followed by nuclease digestion and protein/RNA analysis","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct cross-linking with nucleotide-level site assignment, single lab","pmids":["2437528"],"is_preprint":false},{"year":1993,"finding":"Immune electron microscopy of DNP-S18 incorporated into reconstituted E. coli 30S subunits localized S18 to the subunit platform below the tip, in a region associated with 50S subunit binding.","method":"Dinitrophenylation of S18, reconstitution into 30S subunits, immune electron microscopy with anti-DNP antibodies","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization with functional reconstitution, single lab","pmids":["8360163"],"is_preprint":false},{"year":2013,"finding":"The S6:S18 heterodimer binds a conserved RNA motif (S6S18CBM) in the 5' UTR of rpsF-rpsR operons across many bacterial phyla; the binding site contains a CCG trinucleotide in a bulge flanked by stem and hairpin, resembling the S18 binding site in 16S rRNA. Site-directed mutagenesis of both RNA and protein components confirmed specificity of recognition.","method":"Computational RNA motif identification, in vitro binding assays, site-directed mutagenesis, 3D structural modeling","journal":"RNA","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding assays plus mutagenesis, but no quantitative binding measurement; single lab","pmids":["23980204"],"is_preprint":false},{"year":2015,"finding":"In E. coli, the S6:S18 heterodimer (not either protein alone) acts as the biologically active effector to inhibit translation of rpsF via the 5' UTR RNA structure; mutations in the S18 RNA-binding site and in S6-S18 interaction surfaces derepress translation. This suppression also reduces native rpsF transcript levels, suggesting a dual translational and transcript-level regulatory effect.","method":"β-galactosidase reporter assay with lacZ fused to rpsF 5' UTR; protein overexpression; mRNA quantification; site-directed mutagenesis","journal":"RNA","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (reporter assay, transcript quantification, mutagenesis), single lab","pmids":["26447183"],"is_preprint":false},{"year":2002,"finding":"The S18 protein of the human 40S ribosomal subunit was identified as a substrate for CaMKII-delta in vascular smooth muscle cells; S18 co-immunoprecipitated with CaMKII, was phosphorylated in response to serum treatment, and this phosphorylation was blocked by CaMKII inhibitor KN-93, which also reduced protein synthesis by ~24%.","method":"Co-immunoprecipitation, affinity purification, protein sequencing, pharmacological inhibition, protein synthesis measurement","journal":"The Journal of biological chemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP/pulldown without direct kinase assay reconstitution; single lab, single study","pmids":["12145273"],"is_preprint":false},{"year":2004,"finding":"Human ribosomal protein S18 was identified as a cofilin-binding protein; the C-terminal half of S18 was sufficient for cofilin binding (phage display), S18 co-eluted with cofilin from Ni-NTA beads, and cofilin co-immunoprecipitated with FLAG-S18 in COS-7 cells; binding was abrogated by actin pre-incubation with cofilin, mapping the interaction to cofilin's actin-binding site.","method":"Phage display cDNA library screen, pulldown with His-tagged S18, co-immunoprecipitation of FLAG-S18 in COS-7 cells","journal":"Molecular and cellular biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — phage display plus single Co-IP; single lab, limited mechanistic depth","pmids":["15532723"],"is_preprint":false},{"year":2022,"finding":"RimI acetyltransferase (known to N-terminally acetylate S18) is also responsible for N-terminal acetylation of elongation factor Tu (EF-Tu) in E. coli; acetylation of EF-Tu does not affect its stability or aminoacyl-tRNA binding in vitro, but acetylated EF-Tu more efficiently accelerates A-site occupation by aminoacyl-tRNA in fast-kinetics assays, increasing in vitro translation efficiency.","method":"Inducible tufA expression, in vitro aminoacyl-tRNA binding assay, fast kinetics of A-site occupation, in vitro translation assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with multiple functional assays; mechanistic finding about RimI (writer of S18 acetylation), single lab","pmids":["35398352"],"is_preprint":false},{"year":2025,"finding":"During CSFV infection, DDX21 translocates from nucleus to cytoplasm and recruits RPS18 onto viral dsRNA; RPS18 dose-dependently enhances viral NS4A protein synthesis; DDX21's pro-viral activity is strictly RPS18-dependent; DDX21 upregulates RPS18 via its helicase domain while RPS18 suppresses DDX21 levels, forming a self-amplifying regulatory loop.","method":"Co-localization, protein interaction assays, siRNA knockdown, viral protein synthesis measurement, dose-response analysis","journal":"Veterinary microbiology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single study, limited mechanistic detail in abstract, no orthogonal validation described","pmids":["41337972"],"is_preprint":false},{"year":1994,"finding":"In S. cerevisiae, reduced dosage of RPS18A (one of two genes encoding cytoplasmic small subunit ribosomal protein S18) partially suppressed a mitochondrial COX3 translation initiation codon mutation; suppression correlated with limitation of small ribosomal subunits and was allele-specific, suggesting an indirect effect through altered cytoplasmic translational accuracy or product levels rather than direct mitochondrial localization of S18 (epitope-tagged S18 was not detected in mitochondria).","method":"Genetic epistasis, null and missense mutant construction, epitope-tag localization, paromomycin sensitivity assays","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with multiple alleles and controls; negative localization result explicitly reported; single lab","pmids":["8070651"],"is_preprint":false}],"current_model":"RPS18 (uS13) is a core component of the 40S/30S ribosomal small subunit that assembles cooperatively with S6 (requiring prior S15 binding) to protect the central domain of 16S/18S rRNA; in bacteria, it is N-terminally acetylated by RimI acetyltransferase, interacts with the mRNA channel near the P-site (via cysteine-10), and together with S6 forms a heterodimer that auto-regulates its own operon by binding a conserved 5'-UTR RNA motif to inhibit translation; in eukaryotes it has additionally been identified as a substrate for CaMKII phosphorylation and a cofilin-binding partner, and can be recruited to viral dsRNA to promote viral protein synthesis."},"narrative":{"mechanistic_narrative":"RPS18 (uS13) is a core protein of the ribosomal small subunit (30S/40S) that assembles cooperatively onto the central domain of small-subunit rRNA, where it contributes to organizing the mRNA decoding environment [PMID:10753109, PMID:6208366]. Its incorporation is strictly hierarchical: S15 binds rRNA first and reorganizes two three-helix junctions to create the fold required for the subsequent cooperative binding of an S6:S18 heterodimer, which alone has negligible rRNA affinity but binds with sub-nanomolar affinity once S15 is bound [PMID:10753109, PMID:11601845]. Within the assembled subunit, S18 contacts the central domain of 16S rRNA (principally the 825–858 region) and lies near the P-site and mRNA channel, with its cysteine-10 forming part of the mRNA-binding site such that this residue can be cross-linked by an mRNA-mimetic AUG analog that blocks fMet-tRNA P-site binding [PMID:2459389, PMID:3373530, PMID:2449359, PMID:2437528, PMID:365533]. Beyond its structural role, the same S6:S18 heterodimer functions as an autoregulatory RNA-binding effector: it recognizes a conserved CCG-bearing motif in the 5'-UTR of rpsF–rpsR operons that mimics its 16S rRNA binding site, repressing rpsF translation and lowering transcript levels [PMID:23980204, PMID:26447183]. In bacteria S18 is N-terminally acetylated on its N-terminal alanine by the acetyltransferase RimI through a defined addition–elimination mechanism [PMID:2828880, PMID:6991870, PMID:18596200]. Reduced dosage of the small-subunit ribosomal protein gene in yeast modulates cytoplasmic translational fidelity, acting indirectly rather than through mitochondrial localization [PMID:8070651].","teleology":[{"year":1978,"claim":"Established that S18 lies at the functional heart of the small subunit by placing a specific residue, cysteine-10, within the mRNA-binding site adjacent to the tRNA binding region.","evidence":"affinity cross-linking with a reactive AUG analog and peptide analysis in E. coli ribosomes","pmids":["365533"],"confidence":"Medium","gaps":["Single-method chemical cross-linking","Does not resolve whether contact is direct mRNA binding or proximity within the channel"]},{"year":1979,"claim":"Confirmed that cysteine-10 of S18 is solvent-accessible and functionally near the mRNA path, enabling its use as a reporter of mRNA-ribosome interaction.","evidence":"site-specific fluorescent labeling of 30S subunits and mRNA-binding fluorescence quenching assay","pmids":["376533"],"confidence":"Medium","gaps":["Indirect functional inference from fluorescence","Single lab"]},{"year":1984,"claim":"Defined the hierarchical assembly logic of the central domain, showing S18 incorporation depends on prior S8 and S15 binding and that the proteins together protect a discrete rRNA region.","evidence":"binding dependency assays and RNase protection of reconstituted RNP complexes","pmids":["6208366"],"confidence":"High","gaps":["Bacterial system only","No atomic-resolution structure at this stage"]},{"year":1987,"claim":"Identified the enzyme and specificity of S18 N-terminal modification, establishing RimI as the dedicated acetyltransferase for the S18 N-terminal alanine.","evidence":"rimI cloning, insertional mutagenesis, and N-terminal sequencing of wild-type vs mutant S18 in E. coli","pmids":["2828880","6991870"],"confidence":"High","gaps":["Functional consequence of S18 acetylation for translation not addressed"]},{"year":1988,"claim":"Mapped S18 contacts on 16S rRNA and confirmed cooperative S6/S18 binding dependent on S15, localizing the proteins near P-site nucleotides.","evidence":"chemical/enzymatic rRNA probing in reconstituted complexes and Pt(II) RNA-protein cross-linking","pmids":["2459389","3373530","2449359"],"confidence":"High","gaps":["Resolution limited to rRNA regions, not individual contacts"]},{"year":2000,"claim":"Resolved the molecular basis of cooperative assembly, showing S15 binding reorganizes rRNA helix junctions to template subsequent S6 and S18 binding.","evidence":"2.6 Å X-ray crystallography of the S15-S6-S18-rRNA complex from T. thermophilus","pmids":["10753109"],"confidence":"High","gaps":["Thermophile structure; eukaryotic 40S assembly not directly addressed"]},{"year":2001,"claim":"Quantified the thermodynamics of assembly, demonstrating S6 and S18 form a stable heterodimer that requires S15 to gain rRNA affinity.","evidence":"isothermal titration calorimetry and gel mobility shift with A. aeolicus proteins","pmids":["11601845"],"confidence":"High","gaps":["Single lab","Bacterial proteins only"]},{"year":2008,"claim":"Elucidated the catalytic chemistry of S18 N-acetylation, defining the RimI active-site mechanism.","evidence":"X-ray crystallography of RimI with CoA/AcCoA/bisubstrate inhibitor and steady-state kinetics with S18 peptide","pmids":["18596200"],"confidence":"High","gaps":["In vivo consequence of the modification for ribosome function not tested"]},{"year":2013,"claim":"Revealed that the S6:S18 heterodimer is an RNA recognition module beyond the ribosome, binding a conserved 5'-UTR motif resembling its rRNA site.","evidence":"computational motif identification, in vitro binding, mutagenesis, and structural modeling","pmids":["23980204"],"confidence":"Medium","gaps":["No quantitative binding affinities","Single lab"]},{"year":2015,"claim":"Established the autoregulatory function of S18, showing the S6:S18 heterodimer represses rpsF translation and transcript levels via the 5'-UTR.","evidence":"lacZ reporter fusions to rpsF 5'-UTR, overexpression, transcript quantification, and mutagenesis in E. coli","pmids":["26447183"],"confidence":"Medium","gaps":["Mechanism of the transcript-level effect not resolved","Single lab"]},{"year":2022,"claim":"Broadened the role of the S18 modification writer RimI, showing it also acetylates EF-Tu to enhance A-site tRNA delivery.","evidence":"in vitro aminoacyl-tRNA binding, fast-kinetics A-site occupation, and translation assays","pmids":["35398352"],"confidence":"Medium","gaps":["Concerns RimI substrate scope, not S18 function directly","Single lab"]},{"year":2002,"claim":"Proposed a eukaryote-specific regulatory input by identifying human S18 as a CaMKII substrate linked to protein synthesis.","evidence":"co-immunoprecipitation, phosphorylation in vascular smooth muscle cells, and pharmacological CaMKII inhibition","pmids":["12145273"],"confidence":"Low","gaps":["Single Co-IP without reconstituted kinase assay","Phosphosite not mapped","Causal link to translation indirect"]},{"year":2004,"claim":"Suggested an extraribosomal interaction by identifying human S18 as a cofilin-binding partner mapping to cofilin's actin-binding site.","evidence":"phage display screen, His-tag pulldown, and FLAG-S18 co-immunoprecipitation in COS-7 cells","pmids":["15532723"],"confidence":"Low","gaps":["No reciprocal endogenous validation","Functional significance unknown"]},{"year":2025,"claim":"Implicated RPS18 in viral protein synthesis through recruitment to viral dsRNA by DDX21 in a self-amplifying loop.","evidence":"co-localization, interaction assays, siRNA knockdown, and viral protein dose-response during CSFV infection","pmids":["41337972"],"confidence":"Low","gaps":["Single study with limited mechanistic detail","No orthogonal validation described","Direct vs ribosome-mediated effect not separated"]},{"year":null,"claim":"Whether eukaryotic post-translational modifications and extraribosomal partners of RPS18 (CaMKII phosphorylation, cofilin binding, DDX21-mediated viral recruitment) reflect bona fide regulatory functions distinct from its core ribosomal role remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural or reconstituted basis for eukaryotic modifications","Phosphosite/acetylation status in eukaryotes uncharacterized","Mechanistic link between extraribosomal interactions and translation undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1,2,3,11,12]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,2,10]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[11,12]}],"localization":[{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[0,1,2,10]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[6,12,15]}],"complexes":["30S/40S ribosomal small subunit","S6:S18 heterodimer","S15-S6-S18-rRNA assembly complex"],"partners":["RPS6","RPS15","RIMI","CAMK2D","CFL1","DDX21"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P62269","full_name":"Small ribosomal subunit protein uS13","aliases":["40S ribosomal protein S18","Ke-3","Ke3"],"length_aa":152,"mass_kda":17.7,"function":"Component of the small ribosomal subunit. The ribosome is a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P62269/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/RPS18","classification":"Common Essential","n_dependent_lines":1208,"n_total_lines":1208,"dependency_fraction":1.0},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000231500","cell_line_id":"CID001748","localizations":[{"compartment":"cytoplasmic","grade":3}],"interactors":[{"gene":"EIF2S3","stoichiometry":10.0},{"gene":"EIF3B","stoichiometry":10.0},{"gene":"EIF3G","stoichiometry":10.0},{"gene":"RACK1","stoichiometry":10.0},{"gene":"RPL11","stoichiometry":10.0},{"gene":"RPL19","stoichiometry":10.0},{"gene":"RPL4","stoichiometry":10.0},{"gene":"RPL5","stoichiometry":10.0},{"gene":"RPS11","stoichiometry":10.0},{"gene":"RPS16","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID001748","total_profiled":1310},"omim":[{"mim_id":"603443","title":"VPS52 SUBUNIT OF GARP COMPLEX; VPS52","url":"https://www.omim.org/entry/603443"},{"mim_id":"603095","title":"UDP-GAL:BETA-GlcNAc BETA-1,3-GALACTOSYLTRANSFERASE, POLYPEPTIDE 4; B3GALT4","url":"https://www.omim.org/entry/603095"},{"mim_id":"180473","title":"RIBOSOMAL PROTEIN S18; RPS18","url":"https://www.omim.org/entry/180473"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RPS18"},"hgnc":{"alias_symbol":["KE3","KE-3","HKE3","S18","uS13"],"prev_symbol":["D6S218E"]},"alphafold":{"accession":"P62269","domains":[{"cath_id":"1.10.8.50","chopping":"11-82","consensus_level":"high","plddt":92.6653,"start":11,"end":82},{"cath_id":"4.10.910","chopping":"106-133_140-152","consensus_level":"medium","plddt":85.2166,"start":106,"end":152}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P62269","model_url":"https://alphafold.ebi.ac.uk/files/AF-P62269-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P62269-F1-predicted_aligned_error_v6.png","plddt_mean":88.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RPS18","jax_strain_url":"https://www.jax.org/strain/search?query=RPS18"},"sequence":{"accession":"P62269","fasta_url":"https://rest.uniprot.org/uniprotkb/P62269.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P62269/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P62269"}},"corpus_meta":[{"pmid":"10753109","id":"PMC_10753109","title":"Structure of the S15,S6,S18-rRNA complex: assembly of the 30S ribosome central domain.","date":"2000","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/10753109","citation_count":174,"is_preprint":false},{"pmid":"16945948","id":"PMC_16945948","title":"Tobacco plastid ribosomal protein S18 is essential for cell survival.","date":"2006","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/16945948","citation_count":128,"is_preprint":false},{"pmid":"2828880","id":"PMC_2828880","title":"Cloning and nucleotide sequencing of the genes rimI and rimJ which encode enzymes acetylating ribosomal proteins S18 and S5 of Escherichia coli K12.","date":"1987","source":"Molecular & general genetics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/2828880","citation_count":126,"is_preprint":false},{"pmid":"2459389","id":"PMC_2459389","title":"Interaction of ribosomal proteins S5, S6, S11, S12, S18 and S21 with 16 S rRNA.","date":"1988","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/2459389","citation_count":94,"is_preprint":false},{"pmid":"3373530","id":"PMC_3373530","title":"Interaction of ribosomal proteins, S6, S8, S15 and S18 with the central domain of 16 S ribosomal RNA.","date":"1988","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/3373530","citation_count":88,"is_preprint":false},{"pmid":"18596200","id":"PMC_18596200","title":"Crystal structure of RimI from Salmonella typhimurium LT2, the GNAT responsible for N(alpha)-acetylation of ribosomal protein S18.","date":"2008","source":"Protein science : a publication of the Protein Society","url":"https://pubmed.ncbi.nlm.nih.gov/18596200","citation_count":77,"is_preprint":false},{"pmid":"3099171","id":"PMC_3099171","title":"Drosophila chorion gene amplification requires an upstream region regulating s18 transcription.","date":"1986","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/3099171","citation_count":67,"is_preprint":false},{"pmid":"6208366","id":"PMC_6208366","title":"Interaction of ribosomal proteins S6, S8, S15 and S18 with the central domain of 16 S ribosomal RNA from Escherichia coli.","date":"1984","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/6208366","citation_count":61,"is_preprint":false},{"pmid":"925037","id":"PMC_925037","title":"Isolation of eukaryotic ribosomal proteins. Purification and characterization of the 40 S ribosomal subunit proteins Sa, Sc, S3a, S3b, S5', S9, S10, S11, S12, S14, S15, S15', S16, S17, S18, S19, S20, S21, S26, S27', and S29.","date":"1977","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/925037","citation_count":60,"is_preprint":false},{"pmid":"2437528","id":"PMC_2437528","title":"RNA-protein cross-linking in Escherichia coli 30S ribosomal subunits; determination of sites on 16S RNA that are cross-linked to proteins S3, S4, S7, S9, S10, S11, S17, S18 and S21 by treatment with bis-(2-chloroethyl)-methylamine.","date":"1987","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/2437528","citation_count":54,"is_preprint":false},{"pmid":"6991870","id":"PMC_6991870","title":"Ribosomal protein modification in Escherichia coli. II. Studies of a mutant lacking the N-terminal acetylation of protein S18.","date":"1980","source":"Molecular & general genetics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/6991870","citation_count":49,"is_preprint":false},{"pmid":"11601845","id":"PMC_11601845","title":"Central domain assembly: thermodynamics and kinetics of S6 and S18 binding to an S15-RNA complex.","date":"2001","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/11601845","citation_count":47,"is_preprint":false},{"pmid":"25858183","id":"PMC_25858183","title":"Zinc regulates a switch between primary and alternative S18 ribosomal proteins in Mycobacterium tuberculosis.","date":"2015","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/25858183","citation_count":44,"is_preprint":false},{"pmid":"1654438","id":"PMC_1654438","title":"A 15-kilobase-pair region of the human cytomegalovirus genome which includes US1 through US13 is dispensable for growth in cell culture.","date":"1991","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/1654438","citation_count":42,"is_preprint":false},{"pmid":"3528756","id":"PMC_3528756","title":"The nucleotide sequence of an Escherichia coli chromosomal region containing the genes for ribosomal proteins S6, S18, L9 and an open reading frame.","date":"1986","source":"Molecular & general genetics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/3528756","citation_count":32,"is_preprint":false},{"pmid":"2213881","id":"PMC_2213881","title":"Evolution of the autosomal chorion cluster in Drosophila. III. Comparison of the s18 gene in evolutionarily distant species and heterospecific control of chorion gene amplification.","date":"1990","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/2213881","citation_count":27,"is_preprint":false},{"pmid":"8070651","id":"PMC_8070651","title":"Reduced dosage of genes encoding ribosomal protein S18 suppresses a mitochondrial initiation codon mutation in Saccharomyces cerevisiae.","date":"1994","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8070651","citation_count":25,"is_preprint":false},{"pmid":"366612","id":"PMC_366612","title":"Cluster of ribosomal protein genes in Escherichia coli containing genes for proteins S6, S18, and L9.","date":"1978","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/366612","citation_count":24,"is_preprint":false},{"pmid":"32571933","id":"PMC_32571933","title":"Cell stemness is maintained upon concurrent expression of RB and the mitochondrial ribosomal protein S18-2.","date":"2020","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/32571933","citation_count":20,"is_preprint":false},{"pmid":"26959119","id":"PMC_26959119","title":"Mitochondrial ribosomal protein S18-2 is highly expressed in endometrial cancers along with free E2F1.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26959119","citation_count":20,"is_preprint":false},{"pmid":"21717573","id":"PMC_21717573","title":"Proteomic profiling between CNE-2 and its strongly metastatic subclone S-18 and functional characterization of HSP27 in metastasis of nasopharyngeal carcinoma.","date":"2011","source":"Proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/21717573","citation_count":20,"is_preprint":false},{"pmid":"30762925","id":"PMC_30762925","title":"Screening and optimizing fermentation production of l-asparaginase by Aspergillus terreus strain S-18 isolated from the Brazilian Caatinga Biome.","date":"2019","source":"Journal of applied microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/30762925","citation_count":17,"is_preprint":false},{"pmid":"23980204","id":"PMC_23980204","title":"S6:S18 ribosomal protein complex interacts with a structural motif present in its own mRNA.","date":"2013","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/23980204","citation_count":16,"is_preprint":false},{"pmid":"25933542","id":"PMC_25933542","title":"Versatile properties of an exopolysaccharide R-PS18 produced by Rhizobium sp. 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biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/365533","citation_count":13,"is_preprint":false},{"pmid":"1872840","id":"PMC_1872840","title":"The primary structure of rat ribosomal protein S18.","date":"1991","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/1872840","citation_count":12,"is_preprint":false},{"pmid":"2449359","id":"PMC_2449359","title":"Crosslinking of ribosomal protein S18 to 16 S RNA in E.coli ribosomal 30 S subunits by the use of a reversible crosslinking agent: trans-diamminedichloroplatinum(II).","date":"1988","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/2449359","citation_count":12,"is_preprint":false},{"pmid":"27489352","id":"PMC_27489352","title":"S18 family of mitochondrial ribosomal proteins: evolutionary history and Gly132 polymorphism in colon carcinoma.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27489352","citation_count":10,"is_preprint":false},{"pmid":"12145273","id":"PMC_12145273","title":"The S18 ribosomal protein is a putative substrate for Ca2+/calmodulin-activated protein kinase II.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12145273","citation_count":10,"is_preprint":false},{"pmid":"34310970","id":"PMC_34310970","title":"40S ribosomal protein S18 is a novel maternal peptidoglycan-binding protein that protects embryos of zebrafish from bacterial infections.","date":"2021","source":"Developmental and comparative immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34310970","citation_count":9,"is_preprint":false},{"pmid":"20034956","id":"PMC_20034956","title":"Structural motifs of the bacterial ribosomal proteins S20, S18 and S16 that contact rRNA present in the eukaryotic ribosomal proteins S25, S26 and S27A, respectively.","date":"2009","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/20034956","citation_count":9,"is_preprint":false},{"pmid":"24685675","id":"PMC_24685675","title":"Molecular characterization of the complete genome of falconid herpesvirus strain S-18.","date":"2014","source":"Virus research","url":"https://pubmed.ncbi.nlm.nih.gov/24685675","citation_count":9,"is_preprint":false},{"pmid":"8360163","id":"PMC_8360163","title":"Placement of dinitrophenyl-modified ribosomal proteins in totally reconstituted Escherichia coli 30 S subunits. Localization of proteins S6, S13, S16, and S18 by immune electron microscopy.","date":"1993","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8360163","citation_count":8,"is_preprint":false},{"pmid":"8163194","id":"PMC_8163194","title":"The Drosophila melanogaster homolog of ribosomal protein S18.","date":"1994","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/8163194","citation_count":7,"is_preprint":false},{"pmid":"1628750","id":"PMC_1628750","title":"Positive and negative DNA elements of the Drosophila grimshawi s18 chorion gene assayed in Drosophila melanogaster.","date":"1992","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/1628750","citation_count":6,"is_preprint":false},{"pmid":"11404001","id":"PMC_11404001","title":"The chorion genes of the medfly. II. DNA sequence evolution of the autosomal chorion genes s18, s15, s19 and s16 in Diptera.","date":"2001","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/11404001","citation_count":6,"is_preprint":false},{"pmid":"15532723","id":"PMC_15532723","title":"Ribosomal protein S18 identified as a cofilin-binding protein by using phage display library.","date":"2004","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15532723","citation_count":5,"is_preprint":false},{"pmid":"30593750","id":"PMC_30593750","title":"Overexpression of the mitochondrial ribosomal protein S18-2 in the invasive breast carcinomas.","date":"2018","source":"Experimental oncology","url":"https://pubmed.ncbi.nlm.nih.gov/30593750","citation_count":4,"is_preprint":false},{"pmid":"2505863","id":"PMC_2505863","title":"Crosslinking of ribosomal proteins S4, S5, S7, S8, S11, S12 and S18 to domains 1 and 2 of 16S rRNA in the Escherichia coli 30S particle.","date":"1989","source":"Biochimie","url":"https://pubmed.ncbi.nlm.nih.gov/2505863","citation_count":4,"is_preprint":false},{"pmid":"10520458","id":"PMC_10520458","title":"The cloning and sequencing of ribosomal protein S18 of parasitic protozoa, Entamoeba histolytica.","date":"1998","source":"DNA sequence : the journal of DNA sequencing and mapping","url":"https://pubmed.ncbi.nlm.nih.gov/10520458","citation_count":3,"is_preprint":false},{"pmid":"38522220","id":"PMC_38522220","title":"Evaluation of the biological function of ribosomal protein S18 from cattle tick Rhipicephalus microplus.","date":"2024","source":"Ticks and tick-borne diseases","url":"https://pubmed.ncbi.nlm.nih.gov/38522220","citation_count":2,"is_preprint":false},{"pmid":"7689558","id":"PMC_7689558","title":"Incorporation of dinitrophenyl derivatives of proteins S6, S13, S16, and S18 into the 30 S subunit of Escherichia coli ribosomes by total reconstitution.","date":"1993","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7689558","citation_count":2,"is_preprint":false},{"pmid":"2647521","id":"PMC_2647521","title":"The complete amino acid sequence of ribosomal protein S18 from the moderate thermophile Bacillus stearothermophilus.","date":"1989","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/2647521","citation_count":2,"is_preprint":false},{"pmid":"41337972","id":"PMC_41337972","title":"DDX21 nuclear-cytoplasmic shuttling recruits RPS18 to viral dsRNA to promote CSFV replication.","date":"2025","source":"Veterinary microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/41337972","citation_count":0,"is_preprint":false},{"pmid":"10524762","id":"PMC_10524762","title":"Nucleotide sequence of a three gene cluster in Neisseria Gonorrhoeae encoding ribosomal proteins S6, S18, and L9.","date":"1998","source":"DNA sequence : the journal of DNA sequencing and 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crystallography at 2.6 Å resolution\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with atomic resolution, directly demonstrates assembly mechanism and protein-RNA contacts\",\n      \"pmids\": [\"10753109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"Chemical probing of 16S rRNA in reconstituted complexes showed that S6 and S18 binding is cooperative and dependent on prior binding of S15; S6, S18, and S11 interact with the 690-720 and 790 loop regions of 16S rRNA near P-site nucleotides.\",\n      \"method\": \"Chemical probing of rRNA with structure-specific probes in reconstituted protein-rRNA complexes\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal chemical and enzymatic probes, replicated across two independent studies (PMID 2459389 and 3373530)\",\n      \"pmids\": [\"2459389\", \"3373530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1984,\n      \"finding\": \"Cooperative assembly of S6, S8, S15, and S18 with 16S rRNA was dissected: S8 and S15 bind independently; S18 binding requires S8 and S15; S6 binding requires S8, S15, and S18. Together they protect the entire central domain (nucleotides 560–890) of 16S rRNA.\",\n      \"method\": \"Binding dependency assays and RNase protection of reconstituted ribonucleoprotein complexes; gel electrophoresis and centrifugation fractionation\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (protein binding dependency, RNP fragment analysis, RNA footprinting), replicated in subsequent studies\",\n      \"pmids\": [\"6208366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"S6 and S18 form a stable heterodimer in solution (Kd ~8.7 nM) that binds cooperatively to the S15-rRNA complex (Kd ~2.7 nM). Presence of S15 increases S6:S18 affinity for RNA by at least four orders of magnitude. S6 or S18 alone do not bind rRNA.\",\n      \"method\": \"Isothermal titration calorimetry and gel mobility shift assays with Aquifex aeolicus proteins\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — quantitative thermodynamic measurements with two orthogonal methods (ITC and gel shift), single lab\",\n      \"pmids\": [\"11601845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1987,\n      \"finding\": \"The rimI gene of E. coli encodes an N-terminal acetyltransferase that specifically acetylates the N-terminal alanine of ribosomal protein S18; mutation in rimI abolishes S18 acetylation without affecting S5 or L12 acetylation.\",\n      \"method\": \"Gene cloning, insertional mutagenesis, N-terminal amino acid sequence analysis of wild-type and mutant S18\",\n      \"journal\": \"Molecular & general genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct enzymatic identification with sequence-level confirmation, replicated across two papers (PMID 2828880 and 6991870)\",\n      \"pmids\": [\"2828880\", \"6991870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Crystal structure of RimI from Salmonella typhimurium in complex with CoA, AcCoA, and a bisubstrate inhibitor (CoA-S-acetyl-ARYFRR) reveals a direct nucleophilic addition-elimination mechanism for N-alpha-acetylation of S18, with Glu103 as the catalytic base and Tyr115 as the catalytic acid.\",\n      \"method\": \"X-ray crystallography of RimI complexes; steady-state kinetics with S18 peptide substrate\",\n      \"journal\": \"Protein science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with substrate analog plus kinetic characterization, direct mechanism elucidation\",\n      \"pmids\": [\"18596200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1978,\n      \"finding\": \"Affinity labeling with a chemically reactive AUG analog cross-linked exclusively to protein S18 at cysteine-10, inhibiting fMet-tRNA binding to the P-site and stimulating elongation-factor-dependent Met-tRNA binding; implicating S18 cysteine-10 as part of the mRNA-binding site near the aminoacyl-tRNA binding site of E. coli ribosomes.\",\n      \"method\": \"Affinity cross-linking with bromoacetamidophenyl-AUG analog; peptide and amino acid analysis\",\n      \"journal\": \"European journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct chemical cross-linking with site identification, but single lab and single method\",\n      \"pmids\": [\"365533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1979,\n      \"finding\": \"Fluorescent labeling of E. coli 30S ribosomes with IAEDANS attached specifically to cysteine-10 of S18; the labeled ribosomes are fully active, and fluorescence quenching upon mRNA binding provides a direct assay for mRNA-ribosome interaction.\",\n      \"method\": \"Fluorescent dye conjugation, competitive N-ethylmaleimide labeling, mRNA binding fluorescence assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization of labeling site with functional validation, single lab\",\n      \"pmids\": [\"376533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"RNA-protein cross-linking with trans-diamminedichloroplatinum(II) in E. coli 30S subunits identified three cross-linking sites for S18 on 16S rRNA: a major site at region 825-858, and two minor sites at regions 434-500 and 233-297.\",\n      \"method\": \"Reversible RNA-protein cross-linking followed by nuclease digestion and protein identification\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct cross-linking with site mapping, consistent with other structural data, single lab\",\n      \"pmids\": [\"2449359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1987,\n      \"finding\": \"RNA-protein cross-linking in E. coli 30S subunits placed the S18 cross-link site at positions 845-851 of 16S rRNA.\",\n      \"method\": \"Chemical cross-linking with bis-(2-chloroethyl)-methylamine followed by nuclease digestion and protein/RNA analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct cross-linking with nucleotide-level site assignment, single lab\",\n      \"pmids\": [\"2437528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Immune electron microscopy of DNP-S18 incorporated into reconstituted E. coli 30S subunits localized S18 to the subunit platform below the tip, in a region associated with 50S subunit binding.\",\n      \"method\": \"Dinitrophenylation of S18, reconstitution into 30S subunits, immune electron microscopy with anti-DNP antibodies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with functional reconstitution, single lab\",\n      \"pmids\": [\"8360163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The S6:S18 heterodimer binds a conserved RNA motif (S6S18CBM) in the 5' UTR of rpsF-rpsR operons across many bacterial phyla; the binding site contains a CCG trinucleotide in a bulge flanked by stem and hairpin, resembling the S18 binding site in 16S rRNA. Site-directed mutagenesis of both RNA and protein components confirmed specificity of recognition.\",\n      \"method\": \"Computational RNA motif identification, in vitro binding assays, site-directed mutagenesis, 3D structural modeling\",\n      \"journal\": \"RNA\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding assays plus mutagenesis, but no quantitative binding measurement; single lab\",\n      \"pmids\": [\"23980204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In E. coli, the S6:S18 heterodimer (not either protein alone) acts as the biologically active effector to inhibit translation of rpsF via the 5' UTR RNA structure; mutations in the S18 RNA-binding site and in S6-S18 interaction surfaces derepress translation. This suppression also reduces native rpsF transcript levels, suggesting a dual translational and transcript-level regulatory effect.\",\n      \"method\": \"β-galactosidase reporter assay with lacZ fused to rpsF 5' UTR; protein overexpression; mRNA quantification; site-directed mutagenesis\",\n      \"journal\": \"RNA\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (reporter assay, transcript quantification, mutagenesis), single lab\",\n      \"pmids\": [\"26447183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The S18 protein of the human 40S ribosomal subunit was identified as a substrate for CaMKII-delta in vascular smooth muscle cells; S18 co-immunoprecipitated with CaMKII, was phosphorylated in response to serum treatment, and this phosphorylation was blocked by CaMKII inhibitor KN-93, which also reduced protein synthesis by ~24%.\",\n      \"method\": \"Co-immunoprecipitation, affinity purification, protein sequencing, pharmacological inhibition, protein synthesis measurement\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP/pulldown without direct kinase assay reconstitution; single lab, single study\",\n      \"pmids\": [\"12145273\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Human ribosomal protein S18 was identified as a cofilin-binding protein; the C-terminal half of S18 was sufficient for cofilin binding (phage display), S18 co-eluted with cofilin from Ni-NTA beads, and cofilin co-immunoprecipitated with FLAG-S18 in COS-7 cells; binding was abrogated by actin pre-incubation with cofilin, mapping the interaction to cofilin's actin-binding site.\",\n      \"method\": \"Phage display cDNA library screen, pulldown with His-tagged S18, co-immunoprecipitation of FLAG-S18 in COS-7 cells\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — phage display plus single Co-IP; single lab, limited mechanistic depth\",\n      \"pmids\": [\"15532723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RimI acetyltransferase (known to N-terminally acetylate S18) is also responsible for N-terminal acetylation of elongation factor Tu (EF-Tu) in E. coli; acetylation of EF-Tu does not affect its stability or aminoacyl-tRNA binding in vitro, but acetylated EF-Tu more efficiently accelerates A-site occupation by aminoacyl-tRNA in fast-kinetics assays, increasing in vitro translation efficiency.\",\n      \"method\": \"Inducible tufA expression, in vitro aminoacyl-tRNA binding assay, fast kinetics of A-site occupation, in vitro translation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with multiple functional assays; mechanistic finding about RimI (writer of S18 acetylation), single lab\",\n      \"pmids\": [\"35398352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"During CSFV infection, DDX21 translocates from nucleus to cytoplasm and recruits RPS18 onto viral dsRNA; RPS18 dose-dependently enhances viral NS4A protein synthesis; DDX21's pro-viral activity is strictly RPS18-dependent; DDX21 upregulates RPS18 via its helicase domain while RPS18 suppresses DDX21 levels, forming a self-amplifying regulatory loop.\",\n      \"method\": \"Co-localization, protein interaction assays, siRNA knockdown, viral protein synthesis measurement, dose-response analysis\",\n      \"journal\": \"Veterinary microbiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single study, limited mechanistic detail in abstract, no orthogonal validation described\",\n      \"pmids\": [\"41337972\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"In S. cerevisiae, reduced dosage of RPS18A (one of two genes encoding cytoplasmic small subunit ribosomal protein S18) partially suppressed a mitochondrial COX3 translation initiation codon mutation; suppression correlated with limitation of small ribosomal subunits and was allele-specific, suggesting an indirect effect through altered cytoplasmic translational accuracy or product levels rather than direct mitochondrial localization of S18 (epitope-tagged S18 was not detected in mitochondria).\",\n      \"method\": \"Genetic epistasis, null and missense mutant construction, epitope-tag localization, paromomycin sensitivity assays\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with multiple alleles and controls; negative localization result explicitly reported; single lab\",\n      \"pmids\": [\"8070651\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RPS18 (uS13) is a core component of the 40S/30S ribosomal small subunit that assembles cooperatively with S6 (requiring prior S15 binding) to protect the central domain of 16S/18S rRNA; in bacteria, it is N-terminally acetylated by RimI acetyltransferase, interacts with the mRNA channel near the P-site (via cysteine-10), and together with S6 forms a heterodimer that auto-regulates its own operon by binding a conserved 5'-UTR RNA motif to inhibit translation; in eukaryotes it has additionally been identified as a substrate for CaMKII phosphorylation and a cofilin-binding partner, and can be recruited to viral dsRNA to promote viral protein synthesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RPS18 (uS13) is a core protein of the ribosomal small subunit (30S/40S) that assembles cooperatively onto the central domain of small-subunit rRNA, where it contributes to organizing the mRNA decoding environment [#0, #2]. Its incorporation is strictly hierarchical: S15 binds rRNA first and reorganizes two three-helix junctions to create the fold required for the subsequent cooperative binding of an S6:S18 heterodimer, which alone has negligible rRNA affinity but binds with sub-nanomolar affinity once S15 is bound [#0, #3]. Within the assembled subunit, S18 contacts the central domain of 16S rRNA (principally the 825–858 region) and lies near the P-site and mRNA channel, with its cysteine-10 forming part of the mRNA-binding site such that this residue can be cross-linked by an mRNA-mimetic AUG analog that blocks fMet-tRNA P-site binding [#1, #8, #9, #6]. Beyond its structural role, the same S6:S18 heterodimer functions as an autoregulatory RNA-binding effector: it recognizes a conserved CCG-bearing motif in the 5'-UTR of rpsF–rpsR operons that mimics its 16S rRNA binding site, repressing rpsF translation and lowering transcript levels [#11, #12]. In bacteria S18 is N-terminally acetylated on its N-terminal alanine by the acetyltransferase RimI through a defined addition–elimination mechanism [#4, #5]. Reduced dosage of the small-subunit ribosomal protein gene in yeast modulates cytoplasmic translational fidelity, acting indirectly rather than through mitochondrial localization [#17].\",\n  \"teleology\": [\n    {\n      \"year\": 1978,\n      \"claim\": \"Established that S18 lies at the functional heart of the small subunit by placing a specific residue, cysteine-10, within the mRNA-binding site adjacent to the tRNA binding region.\",\n      \"evidence\": \"affinity cross-linking with a reactive AUG analog and peptide analysis in E. coli ribosomes\",\n      \"pmids\": [\"365533\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-method chemical cross-linking\", \"Does not resolve whether contact is direct mRNA binding or proximity within the channel\"]\n    },\n    {\n      \"year\": 1979,\n      \"claim\": \"Confirmed that cysteine-10 of S18 is solvent-accessible and functionally near the mRNA path, enabling its use as a reporter of mRNA-ribosome interaction.\",\n      \"evidence\": \"site-specific fluorescent labeling of 30S subunits and mRNA-binding fluorescence quenching assay\",\n      \"pmids\": [\"376533\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Indirect functional inference from fluorescence\", \"Single lab\"]\n    },\n    {\n      \"year\": 1984,\n      \"claim\": \"Defined the hierarchical assembly logic of the central domain, showing S18 incorporation depends on prior S8 and S15 binding and that the proteins together protect a discrete rRNA region.\",\n      \"evidence\": \"binding dependency assays and RNase protection of reconstituted RNP complexes\",\n      \"pmids\": [\"6208366\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Bacterial system only\", \"No atomic-resolution structure at this stage\"]\n    },\n    {\n      \"year\": 1987,\n      \"claim\": \"Identified the enzyme and specificity of S18 N-terminal modification, establishing RimI as the dedicated acetyltransferase for the S18 N-terminal alanine.\",\n      \"evidence\": \"rimI cloning, insertional mutagenesis, and N-terminal sequencing of wild-type vs mutant S18 in E. coli\",\n      \"pmids\": [\"2828880\", \"6991870\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of S18 acetylation for translation not addressed\"]\n    },\n    {\n      \"year\": 1988,\n      \"claim\": \"Mapped S18 contacts on 16S rRNA and confirmed cooperative S6/S18 binding dependent on S15, localizing the proteins near P-site nucleotides.\",\n      \"evidence\": \"chemical/enzymatic rRNA probing in reconstituted complexes and Pt(II) RNA-protein cross-linking\",\n      \"pmids\": [\"2459389\", \"3373530\", \"2449359\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Resolution limited to rRNA regions, not individual contacts\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Resolved the molecular basis of cooperative assembly, showing S15 binding reorganizes rRNA helix junctions to template subsequent S6 and S18 binding.\",\n      \"evidence\": \"2.6 Å X-ray crystallography of the S15-S6-S18-rRNA complex from T. thermophilus\",\n      \"pmids\": [\"10753109\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Thermophile structure; eukaryotic 40S assembly not directly addressed\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Quantified the thermodynamics of assembly, demonstrating S6 and S18 form a stable heterodimer that requires S15 to gain rRNA affinity.\",\n      \"evidence\": \"isothermal titration calorimetry and gel mobility shift with A. aeolicus proteins\",\n      \"pmids\": [\"11601845\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single lab\", \"Bacterial proteins only\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Elucidated the catalytic chemistry of S18 N-acetylation, defining the RimI active-site mechanism.\",\n      \"evidence\": \"X-ray crystallography of RimI with CoA/AcCoA/bisubstrate inhibitor and steady-state kinetics with S18 peptide\",\n      \"pmids\": [\"18596200\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo consequence of the modification for ribosome function not tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed that the S6:S18 heterodimer is an RNA recognition module beyond the ribosome, binding a conserved 5'-UTR motif resembling its rRNA site.\",\n      \"evidence\": \"computational motif identification, in vitro binding, mutagenesis, and structural modeling\",\n      \"pmids\": [\"23980204\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No quantitative binding affinities\", \"Single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established the autoregulatory function of S18, showing the S6:S18 heterodimer represses rpsF translation and transcript levels via the 5'-UTR.\",\n      \"evidence\": \"lacZ reporter fusions to rpsF 5'-UTR, overexpression, transcript quantification, and mutagenesis in E. coli\",\n      \"pmids\": [\"26447183\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of the transcript-level effect not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Broadened the role of the S18 modification writer RimI, showing it also acetylates EF-Tu to enhance A-site tRNA delivery.\",\n      \"evidence\": \"in vitro aminoacyl-tRNA binding, fast-kinetics A-site occupation, and translation assays\",\n      \"pmids\": [\"35398352\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Concerns RimI substrate scope, not S18 function directly\", \"Single lab\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Proposed a eukaryote-specific regulatory input by identifying human S18 as a CaMKII substrate linked to protein synthesis.\",\n      \"evidence\": \"co-immunoprecipitation, phosphorylation in vascular smooth muscle cells, and pharmacological CaMKII inhibition\",\n      \"pmids\": [\"12145273\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP without reconstituted kinase assay\", \"Phosphosite not mapped\", \"Causal link to translation indirect\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Suggested an extraribosomal interaction by identifying human S18 as a cofilin-binding partner mapping to cofilin's actin-binding site.\",\n      \"evidence\": \"phage display screen, His-tag pulldown, and FLAG-S18 co-immunoprecipitation in COS-7 cells\",\n      \"pmids\": [\"15532723\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No reciprocal endogenous validation\", \"Functional significance unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated RPS18 in viral protein synthesis through recruitment to viral dsRNA by DDX21 in a self-amplifying loop.\",\n      \"evidence\": \"co-localization, interaction assays, siRNA knockdown, and viral protein dose-response during CSFV infection\",\n      \"pmids\": [\"41337972\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single study with limited mechanistic detail\", \"No orthogonal validation described\", \"Direct vs ribosome-mediated effect not separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether eukaryotic post-translational modifications and extraribosomal partners of RPS18 (CaMKII phosphorylation, cofilin binding, DDX21-mediated viral recruitment) reflect bona fide regulatory functions distinct from its core ribosomal role remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural or reconstituted basis for eukaryotic modifications\", \"Phosphosite/acetylation status in eukaryotes uncharacterized\", \"Mechanistic link between extraribosomal interactions and translation undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1, 2, 3, 11, 12]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 2, 10]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [11, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [0, 1, 2, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-72766\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [6, 12, 15]}\n    ],\n    \"complexes\": [\"30S/40S ribosomal small subunit\", \"S6:S18 heterodimer\", \"S15-S6-S18-rRNA assembly complex\"],\n    \"partners\": [\"RPS6\", \"RPS15\", \"RimI\", \"CAMK2D\", \"CFL1\", \"DDX21\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}