{"gene":"SNU13","run_date":"2026-06-10T07:46:37","timeline":{"discoveries":[{"year":2002,"finding":"15.5K (SNU13) directly binds the box C/D motif of snoRNAs and the 5' stem-loop of U4 snRNA, and this binding is essential for the hierarchical assembly of the box C/D snoRNP; binding of 15.5K is a prerequisite for the subsequent association of NOP56, NOP58, fibrillarin, TIP48, and TIP49. The conserved sequence of stem II of the box C/D motif (but not stem II of U4 5' stem-loop) is required for NOP56, NOP58, fibrillarin, TIP48, and TIP49 binding but not for 15.5K binding, and is essential for nucleolar localization of U14 snoRNA.","method":"In vitro assembly assay with purified components, microinjection of snoRNA into HeLa cells, mutagenesis of stem II","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro reconstitution with mutagenesis plus cell-based localization assay; multiple orthogonal methods in a single rigorous study","pmids":["12417735"],"is_preprint":false},{"year":2003,"finding":"The 15.5K/Snu13p protein independently binds two K-turn motifs in U3 snoRNA: the B/C motif and the C'/D motif. The B/C motif lacks a normal stem I yet shows higher affinity for Snu13p than the C'/D motif. Binding of Snu13p to both motifs is required for U3 snoRNP assembly and activity, and sequence constraints at positions 2 and 3 of the B/C K-turn are more critical for Snu13p binding than corresponding positions in the C'/D K-turn.","method":"Chemical probing of in vitro reconstituted RNA–protein complexes, gel-shift binding assays, phylogenetic analysis, yeast functional assays with base-substituted U3 snoRNA","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (chemical probing, gel-shift, in vivo yeast functional assay) in a single detailed study","pmids":["12810916"],"is_preprint":false},{"year":2002,"finding":"Association of hU3-55K with the U3 snoRNA B/C motif region (U3BC RNA) is strictly dependent on prior binding of 15.5K to the box B/C motif. Additionally, a conserved flanking RNA structure is required for hU3-55K association. hU3-55K directly cross-links to the U3BC RNA, and a structural model places the box B/C motif in a conformation similar to the U4 5' stem-loop and box C/D motif.","method":"In vitro assembly assay, UV cross-linking, deletion/mutagenesis mapping of RNA requirements","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vitro reconstitution with cross-linking and mutagenesis, single lab but multiple orthogonal methods","pmids":["12381732"],"is_preprint":false},{"year":2006,"finding":"15.5K mediates assembly of the U4/U6 snRNP, box C/D snoRNP, and U3 box B/C RNP not only via RNA binding (induced-fit K-turn folding) but also via distinct protein–protein interactions on its surface: different surface regions are required for each RNP complex, and direct protein–protein interaction between hU3-55K and 15.5K was detected.","method":"Systematic surface mutagenesis of 15.5K, in vitro RNP assembly assays, direct protein–protein interaction assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — mutagenesis combined with reconstituted RNP assembly and direct protein–protein binding assays; multiple orthogonal approaches in one study","pmids":["16782898"],"is_preprint":false},{"year":2013,"finding":"Snu13p/15.5K directly interacts with the assembly factor Rsa1p/NUFIP. NMR structure determination and docking identified a specific interface: electrostatic interactions between E72 and D73 of Snu13p and R249, R246, K250 of Rsa1p, shielded by hydrophobic residues, with W253 of Rsa1p inserted into a hydrophobic cavity of Snu13p. This interaction is mutually exclusive with Snu13p contacts in active snoRNPs, and mutations disrupting it impair cell growth and snoRNP formation in yeast.","method":"NMR structure determination, computational docking, biophysical binding assays, site-directed mutagenesis, yeast functional assays (cell growth and snoRNP formation)","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structure plus docking plus mutagenesis plus in vivo functional validation; multiple orthogonal methods in a single rigorous study","pmids":["24234454"],"is_preprint":false},{"year":2005,"finding":"15.5K folds its cognate K-turn RNA (U4 snRNA 5' stem-loop) via an induced-fit mechanism: the free RNA is highly flexible, lacks stable secondary structure elements, and undergoes conformational transitions (loss of G–A base pairs, opening of K-turn) that are suppressed upon 15.5K binding. The protein stabilizes the kinked conformation.","method":"Molecular dynamics simulation, chemical RNA modification experiments","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — combined computational simulation with experimental chemical probing validation; single lab, two methods","pmids":["15659359"],"is_preprint":false},{"year":2007,"finding":"The solution NMR structure of free 15.5K shows a well-structured protein with conformational flexibility confined to helix α3, and limited intermediate/slow motions; this local flexibility may contribute to K-turn RNA recognition and binding.","method":"Solution NMR structure determination, 15N NMR relaxation, H/D exchange experiments","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — NMR structure with dynamics measurements but single lab, no mutagenesis or functional validation of the flexibility","pmids":["18044964"],"is_preprint":false},{"year":2016,"finding":"X-ray crystallographic analysis of Snu13 from the minimal spliceosome of Cyanidioschyzon merolae shows near-identical three-dimensional structure to yeast and human Snu13, consistent with conserved function across highly divergent eukaryotes.","method":"X-ray crystallography","journal":"Protein science : a publication of the Protein Society","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — crystal structure of an ortholog but no functional mutagenesis; structural conservation is the primary finding","pmids":["26833716"],"is_preprint":false},{"year":2019,"finding":"The yeast C/D box snoRNA U14 K-turn motif (kt-U14) adopts a pre-folded conformation in solution resembling the protein-bound K-turn even without divalent ions, with a sharp bend and weak U•U and G•A hydrogen bonds. Snu13p binding further stabilizes this structure. This is distinct from kt-U4, which requires protein or ions to fold.","method":"Solution NMR structure determination, Snu13p binding assay","journal":"Biochimie","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — NMR structure of RNA ± protein binding; single lab but rigorous structural approach with functional context","pmids":["30914254"],"is_preprint":false},{"year":2025,"finding":"Small molecules that bind the K-turn region of the yeast U4 snRNA 5' stem-loop can competitively inhibit binding of U4 snRNA to Snu13, with IC50 = 3.2 ± 0.4 µM for compound 22, demonstrating that the Snu13–U4 snRNA interaction is pharmacologically tractable.","method":"Small molecule microarray screening, biophysical binding assays (deltaSHAPE), biochemical inhibition assay (IC50 determination), MD simulation","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical inhibition assay with experimental deltaSHAPE validation and MD simulation; preprint, single lab","pmids":["bio_10.1101_2025.10.10.681657"],"is_preprint":true}],"current_model":"SNU13/15.5K is a K-turn RNA-binding protein that acts as the nucleation factor for hierarchical assembly of the U4/U6 snRNP, box C/D snoRNPs, and the U3 snoRNA B/C RNP: it binds the K-turn motif via an induced-fit mechanism that folds the RNA, and its surface then presents distinct protein–protein interaction sites that recruit complex-specific partners (hPrp31/61K for U4/U6; NOP56, NOP58, fibrillarin for C/D snoRNP; hU3-55K for U3); its interaction with the assembly factor Rsa1p/NUFIP, whose binding surface on Snu13p is mutually exclusive with active snoRNP contacts, likely prevents premature snoRNP activation during biogenesis."},"narrative":{"mechanistic_narrative":"SNU13 (15.5K/Snu13p) is the universal nucleation factor that initiates hierarchical assembly of K-turn-containing ribonucleoprotein complexes, including the U4/U6 snRNP, box C/D snoRNPs, and the U3 snoRNA RNP [PMID:12417735, PMID:12810916]. It recognizes the K-turn motif through an induced-fit mechanism: the free cognate RNA (e.g. the U4 5' stem-loop) is conformationally flexible and lacks stable structure, and 15.5K binding folds and stabilizes the kinked conformation [PMID:15659359]. Binding of 15.5K is an obligatory first step that licenses subsequent recruitment of complex-specific partners — NOP56, NOP58, fibrillarin, TIP48, and TIP49 for the box C/D snoRNP, with stem II of the box C/D motif required for these downstream associations but not for 15.5K binding itself [PMID:12417735]. For the U3 snoRNP, 15.5K binds two independent K-turns (the B/C and C'/D motifs), and its prior binding to the box B/C motif is strictly required for association of hU3-55K, which it also contacts directly through protein–protein interaction [PMID:12810916, PMID:12381732, PMID:16782898]. Beyond RNA folding, distinct surface regions of 15.5K present separate protein–protein interaction sites that select among U4/U6, C/D snoRNP, and U3 B/C assembly pathways [PMID:16782898]. 15.5K also engages the assembly factor Rsa1p/NUFIP through a defined electrostatic and hydrophobic interface; because this surface overlaps with the contacts used in mature, active snoRNPs, the interaction is mutually exclusive with snoRNP activation and is required for normal cell growth and snoRNP formation [PMID:24234454].","teleology":[{"year":2002,"claim":"Established that 15.5K is the nucleating RNA-binding factor whose binding is a prerequisite for ordered assembly of box C/D snoRNP proteins, defining a hierarchical assembly principle.","evidence":"In vitro assembly with purified components, microinjection of snoRNA into HeLa cells, and stem II mutagenesis","pmids":["12417735"],"confidence":"High","gaps":["Did not resolve the structural basis of K-turn recognition","Mechanism by which stem II recruits NOP56/NOP58/fibrillarin not defined"]},{"year":2002,"claim":"Extended the nucleation principle to the U3 snoRNP by showing that 15.5K binding to the box B/C motif is strictly required for hU3-55K recruitment, with direct RNA cross-linking and a shared K-turn-like conformation.","evidence":"In vitro assembly, UV cross-linking, and deletion/mutagenesis mapping of U3BC RNA","pmids":["12381732"],"confidence":"High","gaps":["Did not identify the protein surface mediating hU3-55K recruitment","Role of the conserved flanking structure mechanistically undefined"]},{"year":2003,"claim":"Showed 15.5K/Snu13p binds two distinct K-turns within U3 snoRNA with differing affinity and sequence constraints, both required for U3 snoRNP assembly and activity.","evidence":"Chemical probing of reconstituted complexes, gel-shift assays, phylogenetics, and yeast functional assays with base-substituted U3","pmids":["12810916"],"confidence":"High","gaps":["Basis for higher B/C affinity despite lacking a normal stem I not structurally resolved","How dual binding is coordinated during assembly unknown"]},{"year":2005,"claim":"Defined the recognition mechanism as induced fit: the cognate U4 K-turn RNA is flexible and unstructured until 15.5K folds and stabilizes the kinked conformation.","evidence":"Molecular dynamics simulation with chemical RNA modification validation","pmids":["15659359"],"confidence":"Medium","gaps":["Computational with limited experimental validation","Did not test the model across all cognate K-turn substrates"]},{"year":2006,"claim":"Demonstrated that 15.5K contributes to assembly beyond RNA binding, using distinct surface regions to present complex-specific protein–protein interaction sites, including a direct contact with hU3-55K.","evidence":"Systematic surface mutagenesis, in vitro RNP assembly, and direct protein–protein interaction assays","pmids":["16782898"],"confidence":"High","gaps":["Did not map full interactomes at each surface","Structural detail of partner docking not resolved"]},{"year":2007,"claim":"Provided the free-protein NMR structure showing 15.5K is well-ordered with flexibility localized to helix α3, implicating that local dynamics in K-turn recognition.","evidence":"Solution NMR structure, 15N relaxation, and H/D exchange","pmids":["18044964"],"confidence":"Medium","gaps":["No mutagenesis linking α3 flexibility to binding","Functional consequence of dynamics not tested"]},{"year":2013,"claim":"Resolved how premature snoRNP activation is avoided: defined the Snu13p–Rsa1p/NUFIP interface and showed it is mutually exclusive with active snoRNP contacts and required for growth and snoRNP formation.","evidence":"NMR structure, docking, biophysical binding, site-directed mutagenesis, and yeast functional assays","pmids":["24234454"],"confidence":"High","gaps":["Timing of the Rsa1p-to-active-snoRNP handoff not directly observed","Other assembly factors at this surface not enumerated"]},{"year":2016,"claim":"Confirmed structural conservation of the Snu13 fold across highly divergent eukaryotes using a minimal spliceosome ortholog.","evidence":"X-ray crystallography of Cyanidioschyzon merolae Snu13","pmids":["26833716"],"confidence":"Medium","gaps":["No functional mutagenesis in this system","Did not test divergent partner interactions"]},{"year":2019,"claim":"Refined the induced-fit model by showing substrate-specific RNA energetics: the C/D U14 K-turn is pre-folded in solution whereas the U4 K-turn requires protein or ions, with Snu13p stabilizing both.","evidence":"Solution NMR structure of kt-U14 ± Snu13p binding","pmids":["30914254"],"confidence":"Medium","gaps":["Functional consequence of pre-folding for assembly kinetics untested","Generality across other C/D K-turns not established"]},{"year":2025,"claim":"Showed the Snu13–U4 snRNA interaction is pharmacologically tractable, with small molecules competitively inhibiting K-turn RNA binding.","evidence":"Small molecule microarray screening, deltaSHAPE, IC50 inhibition assay, and MD simulation (preprint)","pmids":["bio_10.1101_2025.10.10.681657"],"confidence":"Medium","gaps":["Preprint, single lab","Cellular and selectivity effects against other K-turn complexes not demonstrated"]},{"year":null,"claim":"How the timing of the switch from assembly-factor-bound (Rsa1p/NUFIP) intermediates to mature, catalytically engaged snoRNPs is regulated in cells remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No in-cell kinetic trajectory of the assembly-to-activation handoff","Regulatory signals controlling surface occupancy unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1,2,3,5,8]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3,4]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1,3]}],"complexes":["U4/U6 snRNP","box C/D snoRNP","U3 snoRNP"],"partners":["NOP56","NOP58","FIBRILLARIN","HU3-55K","RSA1P/NUFIP","TIP48","TIP49"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P55769","full_name":"NHP2-like protein 1","aliases":["High mobility group-like nuclear protein 2 homolog 1","OTK27","SNU13 homolog","hSNU13","U4/U6.U5 small nuclear ribonucleoprotein SNU13","U4/U6.U5 tri-snRNP 15.5 kDa protein"],"length_aa":128,"mass_kda":14.2,"function":"Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome (PubMed:34516797). Involved in pre-mRNA splicing as component of the spliceosome (PubMed:28781166). Binds to the 5'-stem-loop of U4 snRNA and thereby contributes to spliceosome assembly (PubMed:10545122, PubMed:17412961). The protein undergoes a conformational change upon RNA-binding (PubMed:10545122, PubMed:17412961, PubMed:28781166). Core component of box C/D small nucleolar ribonucleoprotein (snoRNP) complexes that function in methylation of multiple sites on ribosomal RNAs (rRNAs) and messenger RNAs (mRNAs) (PubMed:39570315)","subcellular_location":"Nucleus; Nucleus, nucleolus","url":"https://www.uniprot.org/uniprotkb/P55769/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SNU13","classification":"Common Essential","n_dependent_lines":1207,"n_total_lines":1208,"dependency_fraction":0.9991721854304636},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000100138","cell_line_id":"CID001053","localizations":[{"compartment":"nuclear_punctae","grade":3},{"compartment":"nucleolus_fc_dfc","grade":3}],"interactors":[{"gene":"NOP58","stoichiometry":10.0},{"gene":"RAB11A","stoichiometry":4.0},{"gene":"SNRPF","stoichiometry":4.0},{"gene":"CALD1","stoichiometry":0.2},{"gene":"CPSF6","stoichiometry":0.2},{"gene":"FBL","stoichiometry":0.2},{"gene":"POLR2A","stoichiometry":0.2},{"gene":"RBM39","stoichiometry":0.2},{"gene":"RBM42","stoichiometry":0.2},{"gene":"SNRPA","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001053","total_profiled":1310},"omim":[{"mim_id":"620473","title":"ZINC FINGER HIT DOMAIN-CONTAINING PROTEIN 6; ZNHIT6","url":"https://www.omim.org/entry/620473"},{"mim_id":"620013","title":"RIBOSOMAL RNA-PROCESSING 9, U3 SMALL NUCLEOLAR RNA-BINDING PROTEIN; RRP9","url":"https://www.omim.org/entry/620013"},{"mim_id":"616663","title":"SMALL NUCLEOLAR RNA, C/D BOX, 118; SNORD118","url":"https://www.omim.org/entry/616663"},{"mim_id":"614561","title":"LEUKOENCEPHALOPATHY, BRAIN CALCIFICATIONS, AND CYSTS; LCC","url":"https://www.omim.org/entry/614561"},{"mim_id":"601304","title":"SMALL NUCLEAR RIBONUCLEOPROTEIN (U4/U6.U5), SNU13 HOMOLOG; SNU13","url":"https://www.omim.org/entry/601304"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SNU13"},"hgnc":{"alias_symbol":["FA-1","SPAG12","SNRNP15-5","15.5K"],"prev_symbol":["SSFA1","NHP2L1"]},"alphafold":{"accession":"P55769","domains":[{"cath_id":"3.30.1330.30","chopping":"15-124","consensus_level":"high","plddt":97.1237,"start":15,"end":124}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P55769","model_url":"https://alphafold.ebi.ac.uk/files/AF-P55769-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P55769-F1-predicted_aligned_error_v6.png","plddt_mean":94.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SNU13","jax_strain_url":"https://www.jax.org/strain/search?query=SNU13"},"sequence":{"accession":"P55769","fasta_url":"https://rest.uniprot.org/uniprotkb/P55769.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P55769/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P55769"}},"corpus_meta":[{"pmid":"12417735","id":"PMC_12417735","title":"Conserved stem II of the box C/D motif is essential for nucleolar localization and is required, along with the 15.5K protein, for the hierarchical assembly of the box C/D snoRNP.","date":"2002","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/12417735","citation_count":174,"is_preprint":false},{"pmid":"3316276","id":"PMC_3316276","title":"Involvement of fertilization antigen (FA-1) in involuntary immunoinfertility in humans.","date":"1987","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/3316276","citation_count":78,"is_preprint":false},{"pmid":"3224746","id":"PMC_3224746","title":"Two fetal antigens (FA-1 and FA-2) and endometrial proteins (PP12 and PP14) isolated from amniotic fluid; preliminary observations in fetal and maternal tissues.","date":"1988","source":"European journal of obstetrics, gynecology, and reproductive biology","url":"https://pubmed.ncbi.nlm.nih.gov/3224746","citation_count":75,"is_preprint":false},{"pmid":"12810916","id":"PMC_12810916","title":"A structural, phylogenetic, and functional study of 15.5-kD/Snu13 protein binding on U3 small nucleolar RNA.","date":"2003","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/12810916","citation_count":58,"is_preprint":false},{"pmid":"7534465","id":"PMC_7534465","title":"Molecular identities of human sperm proteins that bind human zona pellucida: nature of sperm-zona interaction, tyrosine kinase activity, and involvement of FA-1.","date":"1994","source":"Molecular reproduction and development","url":"https://pubmed.ncbi.nlm.nih.gov/7534465","citation_count":50,"is_preprint":false},{"pmid":"15006749","id":"PMC_15006749","title":"Characterization of the arginine deiminase operon of Streptococcus rattus FA-1.","date":"2004","source":"Applied and environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/15006749","citation_count":44,"is_preprint":false},{"pmid":"2469607","id":"PMC_2469607","title":"Two fetal antigens (FA-1 and FA-2) and endometrial proteins (PP12 and PP14) isolated from amniotic fluid: localisation in the fetus and adult female genital tract.","date":"1989","source":"European journal of obstetrics, gynecology, and reproductive biology","url":"https://pubmed.ncbi.nlm.nih.gov/2469607","citation_count":43,"is_preprint":false},{"pmid":"16782898","id":"PMC_16782898","title":"Protein-protein and protein-RNA contacts both contribute to the 15.5K-mediated assembly of the U4/U6 snRNP and the box C/D snoRNPs.","date":"2006","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16782898","citation_count":41,"is_preprint":false},{"pmid":"3625608","id":"PMC_3625608","title":"The fertilization antigen (FA-1) causes a reduction of fertility in actively immunized female rabbits.","date":"1987","source":"Journal of reproductive immunology","url":"https://pubmed.ncbi.nlm.nih.gov/3625608","citation_count":39,"is_preprint":false},{"pmid":"28464500","id":"PMC_28464500","title":"CsI Pre-Intercalation in the Inorganic Framework for Efficient and Stable FA1-x Csx PbI3 (Cl) Perovskite Solar Cells.","date":"2017","source":"Small (Weinheim an der Bergstrasse, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/28464500","citation_count":39,"is_preprint":false},{"pmid":"12381732","id":"PMC_12381732","title":"The hU3-55K protein requires 15.5K binding to the box B/C motif as well as flanking RNA elements for its association with the U3 small nucleolar RNA in Vitro.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12381732","citation_count":38,"is_preprint":false},{"pmid":"15659359","id":"PMC_15659359","title":"The snRNP 15.5K protein folds its cognate K-turn RNA: a combined theoretical and biochemical study.","date":"2005","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/15659359","citation_count":37,"is_preprint":false},{"pmid":"24234454","id":"PMC_24234454","title":"Characterization of the interaction between protein Snu13p/15.5K and the Rsa1p/NUFIP factor and demonstration of its functional importance for snoRNP assembly.","date":"2013","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/24234454","citation_count":34,"is_preprint":false},{"pmid":"2673845","id":"PMC_2673845","title":"The detection in human sera of antisperm antibodies reactive with FA-1, an evolutionarily conserved antigen, and with murine spermatozoa.","date":"1989","source":"Fertility and sterility","url":"https://pubmed.ncbi.nlm.nih.gov/2673845","citation_count":31,"is_preprint":false},{"pmid":"1875328","id":"PMC_1875328","title":"Human spermatozoal FA-1 binds with ZP3 of porcine zona pellucida.","date":"1991","source":"Journal of reproductive immunology","url":"https://pubmed.ncbi.nlm.nih.gov/1875328","citation_count":29,"is_preprint":false},{"pmid":"2318530","id":"PMC_2318530","title":"Isolation, characterization, and inhibition kinetics of enolase from Streptococcus rattus FA-1.","date":"1990","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/2318530","citation_count":29,"is_preprint":false},{"pmid":"2372399","id":"PMC_2372399","title":"Antibodies to sperm surface fertilization antigen (FA-1): their specificities and site of interaction with sperm in male genital tract.","date":"1990","source":"Molecular reproduction and development","url":"https://pubmed.ncbi.nlm.nih.gov/2372399","citation_count":28,"is_preprint":false},{"pmid":"8531189","id":"PMC_8531189","title":"Fertilization antigen (FA-1) completely blocks human sperm binding to human zona pellucida: FA-1 antigen may be a sperm receptor for zona pellucida in humans.","date":"1995","source":"Journal of reproductive immunology","url":"https://pubmed.ncbi.nlm.nih.gov/8531189","citation_count":28,"is_preprint":false},{"pmid":"7918868","id":"PMC_7918868","title":"Monoclonal antibody to human fertilization antigen-1 (FA-1) inhibits bovine fertilization in vitro: application in immunocontraception.","date":"1994","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/7918868","citation_count":25,"is_preprint":false},{"pmid":"12203836","id":"PMC_12203836","title":"Molecular cloning and sequencing of cDNA encoding for human FA-1 antigen.","date":"2002","source":"Molecular reproduction and development","url":"https://pubmed.ncbi.nlm.nih.gov/12203836","citation_count":23,"is_preprint":false},{"pmid":"16894551","id":"PMC_16894551","title":"Effect of fertilization antigen (FA-1) DNA vaccine on fertility of female mice.","date":"2006","source":"Molecular reproduction and 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interfaces","url":"https://pubmed.ncbi.nlm.nih.gov/29155561","citation_count":16,"is_preprint":false},{"pmid":"30065307","id":"PMC_30065307","title":"A Novel Compound, \"FA-1\" Isolated from Prunus mume, Protects Human Bronchial Epithelial Cells and Keratinocytes from Cigarette Smoke Extract-Induced Damage.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30065307","citation_count":15,"is_preprint":false},{"pmid":"30914254","id":"PMC_30914254","title":"The yeast C/D box snoRNA U14 adopts a \"weak\" K-turn like conformation recognized by the Snu13 core protein in solution.","date":"2019","source":"Biochimie","url":"https://pubmed.ncbi.nlm.nih.gov/30914254","citation_count":11,"is_preprint":false},{"pmid":"26833716","id":"PMC_26833716","title":"Conserved structure of Snu13 from the highly reduced spliceosome of Cyanidioschyzon merolae.","date":"2016","source":"Protein science : a publication of the Protein 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Fla.)","url":"https://pubmed.ncbi.nlm.nih.gov/40534396","citation_count":3,"is_preprint":false},{"pmid":"35480162","id":"PMC_35480162","title":"Bandgap adjustment assisted preparation of >18% Cs  FA1- PbI  Br3- -based perovskite solar cells using a hybrid spraying process.","date":"2021","source":"RSC advances","url":"https://pubmed.ncbi.nlm.nih.gov/35480162","citation_count":3,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.10.681657","title":"Discovery of small molecule probes targeting the 5′ stem-loop in the yeast U4/U6 snRNA","date":"2025-10-11","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.10.681657","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.10.29.685279","title":"Cellular fitness is determined by ribosomal protein S12-mediated release of a truncated Xrp1","date":"2025-10-30","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.29.685279","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.10.28.685066","title":"Single human fingertip mechanoreceptive afferents simultaneously encode multidimensional aspects of touch","date":"2025-10-29","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.28.685066","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":20284,"output_tokens":2712,"usd":0.050766,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9904,"output_tokens":3200,"usd":0.06476,"stage2_stop_reason":"end_turn"},"total_usd":0.115526,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"15.5K (SNU13) directly binds the box C/D motif of snoRNAs and the 5' stem-loop of U4 snRNA, and this binding is essential for the hierarchical assembly of the box C/D snoRNP; binding of 15.5K is a prerequisite for the subsequent association of NOP56, NOP58, fibrillarin, TIP48, and TIP49. The conserved sequence of stem II of the box C/D motif (but not stem II of U4 5' stem-loop) is required for NOP56, NOP58, fibrillarin, TIP48, and TIP49 binding but not for 15.5K binding, and is essential for nucleolar localization of U14 snoRNA.\",\n      \"method\": \"In vitro assembly assay with purified components, microinjection of snoRNA into HeLa cells, mutagenesis of stem II\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro reconstitution with mutagenesis plus cell-based localization assay; multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"12417735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The 15.5K/Snu13p protein independently binds two K-turn motifs in U3 snoRNA: the B/C motif and the C'/D motif. The B/C motif lacks a normal stem I yet shows higher affinity for Snu13p than the C'/D motif. Binding of Snu13p to both motifs is required for U3 snoRNP assembly and activity, and sequence constraints at positions 2 and 3 of the B/C K-turn are more critical for Snu13p binding than corresponding positions in the C'/D K-turn.\",\n      \"method\": \"Chemical probing of in vitro reconstituted RNA–protein complexes, gel-shift binding assays, phylogenetic analysis, yeast functional assays with base-substituted U3 snoRNA\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (chemical probing, gel-shift, in vivo yeast functional assay) in a single detailed study\",\n      \"pmids\": [\"12810916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Association of hU3-55K with the U3 snoRNA B/C motif region (U3BC RNA) is strictly dependent on prior binding of 15.5K to the box B/C motif. Additionally, a conserved flanking RNA structure is required for hU3-55K association. hU3-55K directly cross-links to the U3BC RNA, and a structural model places the box B/C motif in a conformation similar to the U4 5' stem-loop and box C/D motif.\",\n      \"method\": \"In vitro assembly assay, UV cross-linking, deletion/mutagenesis mapping of RNA requirements\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro reconstitution with cross-linking and mutagenesis, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"12381732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"15.5K mediates assembly of the U4/U6 snRNP, box C/D snoRNP, and U3 box B/C RNP not only via RNA binding (induced-fit K-turn folding) but also via distinct protein–protein interactions on its surface: different surface regions are required for each RNP complex, and direct protein–protein interaction between hU3-55K and 15.5K was detected.\",\n      \"method\": \"Systematic surface mutagenesis of 15.5K, in vitro RNP assembly assays, direct protein–protein interaction assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — mutagenesis combined with reconstituted RNP assembly and direct protein–protein binding assays; multiple orthogonal approaches in one study\",\n      \"pmids\": [\"16782898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Snu13p/15.5K directly interacts with the assembly factor Rsa1p/NUFIP. NMR structure determination and docking identified a specific interface: electrostatic interactions between E72 and D73 of Snu13p and R249, R246, K250 of Rsa1p, shielded by hydrophobic residues, with W253 of Rsa1p inserted into a hydrophobic cavity of Snu13p. This interaction is mutually exclusive with Snu13p contacts in active snoRNPs, and mutations disrupting it impair cell growth and snoRNP formation in yeast.\",\n      \"method\": \"NMR structure determination, computational docking, biophysical binding assays, site-directed mutagenesis, yeast functional assays (cell growth and snoRNP formation)\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structure plus docking plus mutagenesis plus in vivo functional validation; multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"24234454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"15.5K folds its cognate K-turn RNA (U4 snRNA 5' stem-loop) via an induced-fit mechanism: the free RNA is highly flexible, lacks stable secondary structure elements, and undergoes conformational transitions (loss of G–A base pairs, opening of K-turn) that are suppressed upon 15.5K binding. The protein stabilizes the kinked conformation.\",\n      \"method\": \"Molecular dynamics simulation, chemical RNA modification experiments\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — combined computational simulation with experimental chemical probing validation; single lab, two methods\",\n      \"pmids\": [\"15659359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The solution NMR structure of free 15.5K shows a well-structured protein with conformational flexibility confined to helix α3, and limited intermediate/slow motions; this local flexibility may contribute to K-turn RNA recognition and binding.\",\n      \"method\": \"Solution NMR structure determination, 15N NMR relaxation, H/D exchange experiments\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — NMR structure with dynamics measurements but single lab, no mutagenesis or functional validation of the flexibility\",\n      \"pmids\": [\"18044964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"X-ray crystallographic analysis of Snu13 from the minimal spliceosome of Cyanidioschyzon merolae shows near-identical three-dimensional structure to yeast and human Snu13, consistent with conserved function across highly divergent eukaryotes.\",\n      \"method\": \"X-ray crystallography\",\n      \"journal\": \"Protein science : a publication of the Protein Society\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — crystal structure of an ortholog but no functional mutagenesis; structural conservation is the primary finding\",\n      \"pmids\": [\"26833716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The yeast C/D box snoRNA U14 K-turn motif (kt-U14) adopts a pre-folded conformation in solution resembling the protein-bound K-turn even without divalent ions, with a sharp bend and weak U•U and G•A hydrogen bonds. Snu13p binding further stabilizes this structure. This is distinct from kt-U4, which requires protein or ions to fold.\",\n      \"method\": \"Solution NMR structure determination, Snu13p binding assay\",\n      \"journal\": \"Biochimie\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure of RNA ± protein binding; single lab but rigorous structural approach with functional context\",\n      \"pmids\": [\"30914254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Small molecules that bind the K-turn region of the yeast U4 snRNA 5' stem-loop can competitively inhibit binding of U4 snRNA to Snu13, with IC50 = 3.2 ± 0.4 µM for compound 22, demonstrating that the Snu13–U4 snRNA interaction is pharmacologically tractable.\",\n      \"method\": \"Small molecule microarray screening, biophysical binding assays (deltaSHAPE), biochemical inhibition assay (IC50 determination), MD simulation\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical inhibition assay with experimental deltaSHAPE validation and MD simulation; preprint, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.10.10.681657\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"SNU13/15.5K is a K-turn RNA-binding protein that acts as the nucleation factor for hierarchical assembly of the U4/U6 snRNP, box C/D snoRNPs, and the U3 snoRNA B/C RNP: it binds the K-turn motif via an induced-fit mechanism that folds the RNA, and its surface then presents distinct protein–protein interaction sites that recruit complex-specific partners (hPrp31/61K for U4/U6; NOP56, NOP58, fibrillarin for C/D snoRNP; hU3-55K for U3); its interaction with the assembly factor Rsa1p/NUFIP, whose binding surface on Snu13p is mutually exclusive with active snoRNP contacts, likely prevents premature snoRNP activation during biogenesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SNU13 (15.5K/Snu13p) is the universal nucleation factor that initiates hierarchical assembly of K-turn-containing ribonucleoprotein complexes, including the U4/U6 snRNP, box C/D snoRNPs, and the U3 snoRNA RNP [#0, #1]. It recognizes the K-turn motif through an induced-fit mechanism: the free cognate RNA (e.g. the U4 5' stem-loop) is conformationally flexible and lacks stable structure, and 15.5K binding folds and stabilizes the kinked conformation [#5]. Binding of 15.5K is an obligatory first step that licenses subsequent recruitment of complex-specific partners — NOP56, NOP58, fibrillarin, TIP48, and TIP49 for the box C/D snoRNP, with stem II of the box C/D motif required for these downstream associations but not for 15.5K binding itself [#0]. For the U3 snoRNP, 15.5K binds two independent K-turns (the B/C and C'/D motifs), and its prior binding to the box B/C motif is strictly required for association of hU3-55K, which it also contacts directly through protein–protein interaction [#1, #2, #3]. Beyond RNA folding, distinct surface regions of 15.5K present separate protein–protein interaction sites that select among U4/U6, C/D snoRNP, and U3 B/C assembly pathways [#3]. 15.5K also engages the assembly factor Rsa1p/NUFIP through a defined electrostatic and hydrophobic interface; because this surface overlaps with the contacts used in mature, active snoRNPs, the interaction is mutually exclusive with snoRNP activation and is required for normal cell growth and snoRNP formation [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established that 15.5K is the nucleating RNA-binding factor whose binding is a prerequisite for ordered assembly of box C/D snoRNP proteins, defining a hierarchical assembly principle.\",\n      \"evidence\": \"In vitro assembly with purified components, microinjection of snoRNA into HeLa cells, and stem II mutagenesis\",\n      \"pmids\": [\"12417735\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the structural basis of K-turn recognition\", \"Mechanism by which stem II recruits NOP56/NOP58/fibrillarin not defined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Extended the nucleation principle to the U3 snoRNP by showing that 15.5K binding to the box B/C motif is strictly required for hU3-55K recruitment, with direct RNA cross-linking and a shared K-turn-like conformation.\",\n      \"evidence\": \"In vitro assembly, UV cross-linking, and deletion/mutagenesis mapping of U3BC RNA\",\n      \"pmids\": [\"12381732\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the protein surface mediating hU3-55K recruitment\", \"Role of the conserved flanking structure mechanistically undefined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showed 15.5K/Snu13p binds two distinct K-turns within U3 snoRNA with differing affinity and sequence constraints, both required for U3 snoRNP assembly and activity.\",\n      \"evidence\": \"Chemical probing of reconstituted complexes, gel-shift assays, phylogenetics, and yeast functional assays with base-substituted U3\",\n      \"pmids\": [\"12810916\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Basis for higher B/C affinity despite lacking a normal stem I not structurally resolved\", \"How dual binding is coordinated during assembly unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined the recognition mechanism as induced fit: the cognate U4 K-turn RNA is flexible and unstructured until 15.5K folds and stabilizes the kinked conformation.\",\n      \"evidence\": \"Molecular dynamics simulation with chemical RNA modification validation\",\n      \"pmids\": [\"15659359\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Computational with limited experimental validation\", \"Did not test the model across all cognate K-turn substrates\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrated that 15.5K contributes to assembly beyond RNA binding, using distinct surface regions to present complex-specific protein–protein interaction sites, including a direct contact with hU3-55K.\",\n      \"evidence\": \"Systematic surface mutagenesis, in vitro RNP assembly, and direct protein–protein interaction assays\",\n      \"pmids\": [\"16782898\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not map full interactomes at each surface\", \"Structural detail of partner docking not resolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Provided the free-protein NMR structure showing 15.5K is well-ordered with flexibility localized to helix α3, implicating that local dynamics in K-turn recognition.\",\n      \"evidence\": \"Solution NMR structure, 15N relaxation, and H/D exchange\",\n      \"pmids\": [\"18044964\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mutagenesis linking α3 flexibility to binding\", \"Functional consequence of dynamics not tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved how premature snoRNP activation is avoided: defined the Snu13p–Rsa1p/NUFIP interface and showed it is mutually exclusive with active snoRNP contacts and required for growth and snoRNP formation.\",\n      \"evidence\": \"NMR structure, docking, biophysical binding, site-directed mutagenesis, and yeast functional assays\",\n      \"pmids\": [\"24234454\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Timing of the Rsa1p-to-active-snoRNP handoff not directly observed\", \"Other assembly factors at this surface not enumerated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Confirmed structural conservation of the Snu13 fold across highly divergent eukaryotes using a minimal spliceosome ortholog.\",\n      \"evidence\": \"X-ray crystallography of Cyanidioschyzon merolae Snu13\",\n      \"pmids\": [\"26833716\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional mutagenesis in this system\", \"Did not test divergent partner interactions\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Refined the induced-fit model by showing substrate-specific RNA energetics: the C/D U14 K-turn is pre-folded in solution whereas the U4 K-turn requires protein or ions, with Snu13p stabilizing both.\",\n      \"evidence\": \"Solution NMR structure of kt-U14 ± Snu13p binding\",\n      \"pmids\": [\"30914254\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of pre-folding for assembly kinetics untested\", \"Generality across other C/D K-turns not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed the Snu13–U4 snRNA interaction is pharmacologically tractable, with small molecules competitively inhibiting K-turn RNA binding.\",\n      \"evidence\": \"Small molecule microarray screening, deltaSHAPE, IC50 inhibition assay, and MD simulation (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.10.10.681657\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, single lab\", \"Cellular and selectivity effects against other K-turn complexes not demonstrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the timing of the switch from assembly-factor-bound (Rsa1p/NUFIP) intermediates to mature, catalytically engaged snoRNPs is regulated in cells remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No in-cell kinetic trajectory of the assembly-to-activation handoff\", \"Regulatory signals controlling surface occupancy unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1, 2, 3, 5, 8]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"complexes\": [\"U4/U6 snRNP\", \"box C/D snoRNP\", \"U3 snoRNP\"],\n    \"partners\": [\"NOP56\", \"NOP58\", \"fibrillarin\", \"hU3-55K\", \"Rsa1p/NUFIP\", \"TIP48\", \"TIP49\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":5,"faith_pct":80.0}}