{"gene":"MPHOSPH10","run_date":"2026-06-10T02:59:51","timeline":{"discoveries":[{"year":1996,"finding":"MPHOSPH10/MPP10 is a nucleolar protein in interphase cells that becomes an M phase phosphoprotein recognized by the MPM2 antibody (which recognizes F-phosphoT-P-L-Q motifs), indicating it is phosphorylated at M phase-specific sites during mitosis. In mitosis, it redistributes throughout the cell.","method":"Immunofluorescence microscopy and immunoprecipitation with MPM2 antibody from M phase cell lysates","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with immunofluorescence and biochemical validation by immunoprecipitation, single lab but two orthogonal methods","pmids":["8885239"],"is_preprint":false},{"year":1997,"finding":"Yeast Mpp10p is a component of the U3 snoRNP: antibodies to purified Mpp10p immunoprecipitate U3 snoRNA from yeast extracts. MPP10 is an essential gene, and depletion of Mpp10p causes accumulation of 23S and 35S pre-rRNA precursors and loss of 18S rRNA and its 20S precursor, demonstrating Mpp10p is required for pre-rRNA cleavage at sites A0, A1, and A2.","method":"Co-immunoprecipitation of U3 snoRNA, conditional promoter depletion, Northern blot analysis of pre-rRNA processing, pulse-chase analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus genetic depletion with defined pre-rRNA processing phenotype, replicated across multiple labs subsequently","pmids":["9315638"],"is_preprint":false},{"year":1997,"finding":"C-terminal truncations of Mpp10p separate U3 snoRNP function into two distinct activities: truncated Mpp10p supports cleavage at A0 but not at A1/A2 sites, without affecting Mpp10p-U3 snoRNA association or protein stability, demonstrating the C-terminus is specifically required for A1/A2 processing.","method":"Truncation mutagenesis, Northern blot pre-rRNA processing analysis, cold-sensitivity growth assay, co-immunoprecipitation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis with defined processing phenotype replicated and extended by subsequent work","pmids":["9391061"],"is_preprint":false},{"year":1998,"finding":"Human MPP10 localizes almost entirely to nucleoli by cell fractionation; by immunofluorescence it co-localizes with nucleolar fibrillarin in interphase but not in coiled bodies. Upon actinomycin D treatment, MPP10 is enriched in fibrillar caps (sites of rRNA processing). In early-to-middle M phase, MPP10 co-localizes with fibrillarin on chromosome surfaces, and at telophase appears in nucleolus-derived bodies and prenucleolar bodies. Immunoprecipitation from cell sonicates shows MPP10 specifically associates with U3 snoRNA but not other box C/D snoRNAs, stable to 400 mM salt, establishing human MPP10 as a U3 snoRNP component.","method":"Cell fractionation, immunofluorescence microscopy, immunoprecipitation of snoRNA, actinomycin D treatment","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (fractionation, immunofluorescence, Co-IP with functional specificity controls) in single study with strong controls","pmids":["9450966"],"is_preprint":false},{"year":1999,"finding":"Imp3p and Imp4p are two novel U3 snoRNP proteins identified by two-hybrid screening for proteins that physically associate with Mpp10p. Both associate with Mpp10p in vivo and are complexed only with U3 snoRNA. Genetic depletion of either Imp3p or Imp4p causes defects in pre-18S rRNA processing at A0, A1, and A2 sites, and neither is required for U3 snoRNA integrity.","method":"Yeast two-hybrid screen, co-immunoprecipitation in vivo, conditional depletion with Northern blot analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — two-hybrid identification confirmed by in vivo Co-IP plus genetic depletion phenotype, replicated in subsequent structural and biochemical studies","pmids":["10409734"],"is_preprint":false},{"year":2001,"finding":"Association of Mpp10p with the U3 snoRNP requires a conserved sequence element in the U3 snoRNA hinge region (nt 40-72), not the 3' domain sufficient for other U3 snoRNP proteins. This places Mpp10p near the 5' domain that carries out pre-rRNA base-pairing interactions, at the functional center of the U3 snoRNP.","method":"U3 snoRNA deletion and truncation analysis by co-immunoprecipitation","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic RNA deletion mapping with Co-IP readout, single lab","pmids":["11421365"],"is_preprint":false},{"year":2002,"finding":"Imp3p, Imp4p, and Mpp10p show interdependence for their stability and their association with U3 snoRNA. C-terminal truncations of Mpp10p combined with U3 snoRNA processing-defective mutations produce a more severe A2 cleavage defect than either alone, indicating Mpp10p acts at an additional mechanistic step beyond U3 snoRNA base-pairing maintenance. The last 95 amino acids of yeast Mpp10p are specifically required for growth and pre-rRNA processing at low temperatures, as shown by failed heterologous complementation without this region.","method":"Genetic epistasis (double-mutant analysis), heterologous complementation, protein stability assays, co-immunoprecipitation","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis analysis combined with complementation and Co-IP, multiple orthogonal approaches in single study","pmids":["12242301"],"is_preprint":false},{"year":2004,"finding":"Binding of Mpp10 to the 80S U3 snoRNP processing complex requires sequences within the U3 snoRNA that base pair with the pre-rRNA adjacent to the initial cleavage site. Mutations that inhibit 80S complex formation and/or Mpp10 association cause retention of U3 snoRNA in the dense fibrillar component (DFC) rather than movement to the granular component (GC), indicating Mpp10 association is linked to U3 snoRNA subnucleolar trafficking.","method":"U3 snoRNA mutational analysis, immunoprecipitation, subnucleolar fractionation","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutational analysis linked to localization phenotype, single lab","pmids":["15367679"],"is_preprint":false},{"year":2004,"finding":"Mpp10p-Imp4p protein-protein interaction was tested by reverse two-hybrid screening; mutations in the N-terminal coiled-coil domain of Imp4 confer cold sensitivity, mutations in C-terminus confer temperature sensitivity. Surprisingly, these mutant Imp4 proteins are not measurably defective for Mpp10p interaction within the intact SSU processome, suggesting other complex members maintain this interaction, while still causing pre-rRNA processing defects.","method":"Reverse two-hybrid system, co-immunoprecipitation within SSU processome context, pre-rRNA Northern blot analysis","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two-hybrid plus in-complex Co-IP with processing phenotype, single lab","pmids":["14990745"],"is_preprint":false},{"year":2007,"finding":"In the 90S preribosome assembly hierarchy, the Mpp10 complex (with Imp3 and Imp4) assembles as a discrete subunit that enters as part of one of two mutually independent assembly routes. This route also involves U3 snoRNP and UTP-B (Pwp2p) subunit binding, which is downstream of the essential t-UTP subunit assembly step.","method":"Biochemical fractionation, proteomics, RNA co-immunoprecipitation, bioinformatic assembly modeling","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical fractionation plus proteomic analysis establishing assembly hierarchy, single lab","pmids":["17515605"],"is_preprint":false},{"year":2009,"finding":"Human MPP10 is part of a distinct subcomplex within the SSU processome. A novel 50S U3 snoRNP intermediate accumulates when pre-rRNA transcription is blocked or tUTP proteins are depleted; this intermediate lacks the tUTP, bUTP, MPP10, and BMS1/RCL1 subcomplexes, establishing that MPP10 complex recruitment to the SSU processome is dependent on active pre-rRNA transcription and prior tUTP assembly.","method":"Sucrose gradient sedimentation, immunoprecipitation, RNAi depletion of tUTP proteins, transcription inhibition","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple depletion conditions plus sedimentation analysis establishing assembly dependence, single lab","pmids":["19332556"],"is_preprint":false},{"year":2011,"finding":"The U3 snoRNA hinge region segment VI (forming an 11-bp helix with 5'-ETS) is essential for pre-rRNA processing and cell growth. Compensatory mutations in helix VI restore growth, and specific sequences within segment VI are required for association of Mpp10, Imp4, and Imp3 proteins, placing these proteins at the U3 snoRNA-pre-rRNA interface.","method":"Compensatory mutation analysis in vivo, co-immunoprecipitation of Mpp10/Imp4/Imp3 with U3 snoRNA variants","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — compensatory mutation rescue plus Co-IP, single lab","pmids":["21890904"],"is_preprint":false},{"year":2016,"finding":"Cryo-EM structure of the Chaetomium thermophilum 90S pre-ribosome identifies the Mpp10-Imp3-Imp4 module as a discrete structural unit within the particle, organized around the 5'-ETS and partially folded 18S rRNA, with the U3 snoRNP positioned centrally.","method":"Cryo-EM structural analysis of 90S pre-ribosome","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure of intact complex, identifies Mpp10 complex position directly","pmids":["27419870"],"is_preprint":false},{"year":2016,"finding":"Mpp10 is a substrate of the yeast arginine methyltransferase Hmt1, validated by ex vivo methylation assay and MS/MS analysis, establishing Mpp10 as an arginine-methylated protein.","method":"Proteome array with anti-methylarginine antibody, ex vivo methylation assay with recombinant Hmt1, MS/MS validation","journal":"Proteomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteome array screen confirmed by ex vivo methylation and MS/MS, single lab but two orthogonal methods","pmids":["26572822"],"is_preprint":false},{"year":2017,"finding":"High-resolution (3.2 Å) cryo-EM structure of the Chaetomium thermophilum 90S preribosome allows atomic model building of the Mpp10 complex. The structure reveals the Mpp10 complex as part of the intertwined assembly factor network that maintains pre-18S RNA domains in an immature state, and identifies the Mpp10 complex in proximity to the unprocessed A1 cleavage site.","method":"Cryo-EM at 3.2 Å resolution with atomic model building","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — near-atomic cryo-EM structure with model building, independent replication of 90S structural studies","pmids":["28967883"],"is_preprint":false},{"year":2017,"finding":"Crystal structure of Imp4 in complex with a short helical element of Mpp10 resolved at 1.88 Å. Additionally, Mpp10 binds Utp3/Sas10 through two conserved motifs in its N-terminal region, and interacts with ribosomal protein S5/uS7 through a short stretch in an acidic loop region, establishing Mpp10 as a multi-protein interaction platform within the 90S pre-ribosome.","method":"X-ray crystallography at 1.88 Å, co-immunoprecipitation, binding assays for novel interactions","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus biochemical validation of multiple novel interactions, multiple orthogonal methods","pmids":["28813493"],"is_preprint":false},{"year":2019,"finding":"Sas10/Utp3 stabilizes Mpp10 from Capn3-mediated cleavage by masking the Capn3-recognition site on Mpp10. Def interacts with Sas10 to form the Def-Sas10-Mpp10 complex, which facilitates Capn3-mediated cleavage of Mpp10. Sas10 is required for nucleolar localization of the Mpp10-Imp3-Imp4 complex, establishing Sas10 as both a chaperone/protector and delivery factor for the Mpp10 complex.","method":"In vivo protein interaction assays (Co-IP), genetic depletion/knockdown in zebrafish, subcellular localization analysis, protein stability assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, localization, stability assays, in vivo genetics) in zebrafish and cellular models, novel mechanistic pathway established","pmids":["30773582"],"is_preprint":false},{"year":2021,"finding":"Mpp10 is a substrate of the nucleolus-localized Def-CAPN3 protein degradation pathway. CAPN3 (Calpain3), recruited to the nucleolus by Def, proteolytically cleaves Mpp10 via a recognition motif on Mpp10. Def depletion leads to accumulation of Mpp10 in the nucleolus and rRNA processing abnormality, establishing Mpp10 turnover as part of cell-cycle control and ribosome biogenesis regulation.","method":"Genetic depletion of Def, subcellular fractionation, protein degradation assays, rRNA processing analysis","journal":"Journal of genetics and genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic depletion with biochemical and rRNA processing readouts, review/summary paper but cites underlying experimental work","pmids":["34452850"],"is_preprint":false},{"year":2022,"finding":"An 86-amino acid motif (430-515 aa) in human CAPN3 is essential for its interaction with human Def, and the corresponding region is conserved in zebrafish Capn3b. The 2/3 C-terminus of human Def mediates the Def-CAPN3 interaction. This Def-CAPN3 complex mediates degradation of Mpp10 in the nucleolus.","method":"Truncation and internal deletion analysis of CAPN3, co-immunoprecipitation of Def-CAPN3 variants","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic deletion mapping by Co-IP, single lab, provides mechanism of Mpp10-relevant degradation complex assembly","pmids":["35878425"],"is_preprint":false},{"year":2023,"finding":"UTP11 binds directly to MPP10 (pre-rRNA processing factor) and is required for 18S rRNA biosynthesis; depletion of UTP11 impedes 18S rRNA production to trigger nucleolar stress.","method":"Co-immunoprecipitation/binding assay between UTP11 and MPP10, rRNA processing analysis upon UTP11 depletion","journal":"Redox biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP/binding claim, single lab, limited mechanistic detail in abstract","pmids":["37087976"],"is_preprint":false},{"year":2024,"finding":"UTP3/SAS10 assists the nucleolar localization of MPP10 (along with UTP25, EMG1, UTP12, and UTP13) through its interaction with nuclear importin α. Knockdown of human UTP3 impairs MPP10 nucleolar localization and cleavage at the pre-rRNA A0-site, establishing a UTP3-dependent nucleolar translocation pathway for MPP10.","method":"Systematic localization screen of 50 SSU processome components by fluorescence microscopy, siRNA knockdown, importin α interaction assay, rRNA processing analysis","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic localization screen plus knockdown with functional readout and importin interaction assay, single lab but multiple orthogonal methods","pmids":["39036955"],"is_preprint":false}],"current_model":"MPHOSPH10/MPP10 is an essential nucleolar protein and core component of the U3 snoRNP/SSU processome that, together with its direct binding partners Imp3 and Imp4, forms a discrete subcomplex within the 90S pre-ribosome required for endonucleolytic cleavage at the A0, A1, and A2 sites of pre-rRNA to produce mature 18S rRNA; Mpp10 acts as a multi-protein interaction platform (also binding Utp3/Sas10 and ribosomal protein uS7), is delivered to the nucleolus via a UTP3/importin-α-dependent pathway, is subject to arginine methylation by Hmt1 and to proteolytic turnover by the Def-CAPN3 nucleolar degradation pathway (with Sas10 protecting Mpp10 from this cleavage), and undergoes M phase-specific phosphorylation that coincides with its redistribution from nucleoli to chromosome surfaces during mitosis."},"narrative":{"mechanistic_narrative":"MPHOSPH10/MPP10 is an essential nucleolar protein that functions as a core component of the U3 snoRNP/SSU processome, where it is required for endonucleolytic cleavage of pre-rRNA at the A0, A1, and A2 sites to generate mature 18S rRNA [PMID:9315638, PMID:9450966]. Within the 90S pre-ribosome, Mpp10 forms a discrete structural module with its direct partners Imp3 and Imp4 — interactions identified by two-hybrid screening, confirmed in vivo, and resolved at atomic resolution by crystallography and cryo-EM — that organizes around the 5'-ETS and immature 18S rRNA near the unprocessed A1 cleavage site [PMID:10409734, PMID:27419870, PMID:28967883, PMID:28813493]. Mpp10 association with the U3 snoRNP depends on a conserved element in the U3 snoRNA hinge region, placing the module at the functional U3 snoRNA–pre-rRNA base-pairing interface, and its C-terminus is specifically required for A1/A2 (but not A0) cleavage, defining a discrete mechanistic role beyond maintenance of U3 base-pairing [PMID:9391061, PMID:11421365, PMID:12242301, PMID:21890904]. Mpp10 acts as a multi-protein interaction platform, additionally binding Utp3/Sas10 and ribosomal protein uS7, and is delivered to the nucleolus through a UTP3/Sas10–importin-α–dependent route required for A0 cleavage [PMID:28813493, PMID:30773582, PMID:39036955]. Mpp10 abundance is controlled by the nucleolar Def–CAPN3 (Calpain3) degradation pathway, with Sas10 protecting Mpp10 by masking the CAPN3 recognition site, and Mpp10 is also subject to arginine methylation by Hmt1 [PMID:26572822, PMID:30773582, PMID:34452850, PMID:35878425]. In interphase Mpp10 is nucleolar, but it becomes an M-phase phosphoprotein and redistributes onto chromosome surfaces during mitosis [PMID:8885239, PMID:9450966].","teleology":[{"year":1996,"claim":"Established MPHOSPH10 as a nucleolar protein that is cell-cycle regulated, becoming an M-phase phosphoprotein that redistributes during mitosis — the first link between this protein and dynamic nuclear/nucleolar behavior.","evidence":"Immunofluorescence and MPM2-antibody immunoprecipitation from M-phase cell lysates","pmids":["8885239"],"confidence":"Medium","gaps":["Kinase responsible for M-phase phosphorylation not identified","Functional consequence of mitotic redistribution unknown"]},{"year":1997,"claim":"Defined the core molecular function: Mpp10 is an essential U3 snoRNP component required for pre-rRNA cleavage at A0, A1, and A2, answering what process the protein serves.","evidence":"U3 snoRNA Co-IP, conditional depletion, Northern blot and pulse-chase analysis of pre-rRNA processing in yeast","pmids":["9315638"],"confidence":"High","gaps":["Did not resolve whether Mpp10 acts catalytically or as a scaffold","Partner proteins within the U3 snoRNP not yet defined"]},{"year":1997,"claim":"Dissected Mpp10 into separable functional domains by showing the C-terminus is specifically required for A1/A2 but not A0 cleavage, establishing distinct mechanistic steps within the protein.","evidence":"C-terminal truncation mutagenesis with pre-rRNA Northern analysis and Co-IP in yeast","pmids":["9391061"],"confidence":"High","gaps":["Molecular basis of A1/A2-specific requirement not defined","C-terminal interaction partners unidentified at this stage"]},{"year":1998,"claim":"Extended the U3 snoRNP role to human MPP10, with detailed subnucleolar localization and U3-specific snoRNA association, showing functional conservation.","evidence":"Cell fractionation, immunofluorescence with fibrillarin, salt-stable snoRNA Co-IP, actinomycin D treatment in human cells","pmids":["9450966"],"confidence":"High","gaps":["Human protein interactors beyond U3 snoRNA not defined","Mechanism of mitotic chromosome-surface localization unresolved"]},{"year":1999,"claim":"Identified the direct binding partners Imp3 and Imp4 as novel U3 snoRNP proteins, revealing Mpp10 operates as part of a defined protein module.","evidence":"Yeast two-hybrid screen, in vivo Co-IP, conditional depletion with Northern analysis","pmids":["10409734"],"confidence":"High","gaps":["Stoichiometry and architecture of the Mpp10-Imp3-Imp4 module not yet known","Direct interfaces between the three proteins not mapped"]},{"year":2001,"claim":"Mapped Mpp10 to the functional center of the U3 snoRNP by showing its association requires the U3 hinge region rather than the 3' domain used by other U3 proteins.","evidence":"U3 snoRNA deletion/truncation mapping by Co-IP","pmids":["11421365"],"confidence":"Medium","gaps":["Direct RNA-protein contact residues not defined","Single-lab RNA mapping"]},{"year":2002,"claim":"Showed interdependent stability and U3 association of Mpp10, Imp3, and Imp4, and via epistasis that Mpp10 acts at a step beyond U3 base-pairing maintenance.","evidence":"Double-mutant epistasis, heterologous complementation, stability assays, Co-IP in yeast","pmids":["12242301"],"confidence":"High","gaps":["Identity of the additional A2 mechanistic step not defined","Temperature-specific requirement of the terminal 95 residues mechanistically unexplained"]},{"year":2004,"claim":"Linked Mpp10 association with the 80S processing complex to U3 snoRNA subnucleolar trafficking from the DFC to the GC.","evidence":"U3 snoRNA mutational analysis, immunoprecipitation, subnucleolar fractionation","pmids":["15367679"],"confidence":"Medium","gaps":["Causality between Mpp10 binding and trafficking not proven","Single-lab data"]},{"year":2004,"claim":"Probed the Mpp10-Imp4 interaction within the intact processome, finding processing-defective Imp4 mutants retain Mpp10 association, implying redundant contacts maintain the module.","evidence":"Reverse two-hybrid, in-complex Co-IP, pre-rRNA Northern analysis","pmids":["14990745"],"confidence":"Medium","gaps":["Other complex members maintaining the interaction not identified","Decoupling of processing defect from interaction loss unexplained"]},{"year":2009,"claim":"Placed the Mpp10 complex in the SSU processome assembly hierarchy, showing its recruitment depends on active pre-rRNA transcription and prior tUTP assembly in both yeast and human systems.","evidence":"Sucrose gradient sedimentation, IP, tUTP RNAi, transcription inhibition (human); biochemical fractionation and assembly modeling (yeast)","pmids":["19332556","17515605"],"confidence":"Medium","gaps":["Direct recruitment signal/receptor for the Mpp10 complex not identified","Single-lab assembly models"]},{"year":2011,"claim":"Refined the RNA contact, showing U3 hinge segment VI (the 11-bp helix with 5'-ETS) is required for Mpp10/Imp3/Imp4 association, positioning the module at the U3-pre-rRNA interface.","evidence":"Compensatory mutation rescue in vivo plus Co-IP with U3 variants","pmids":["21890904"],"confidence":"Medium","gaps":["Direct protein contacts to helix VI not resolved at residue level","Single-lab data"]},{"year":2017,"claim":"Resolved the architecture of the Mpp10 module at atomic detail and revealed Mpp10 as a multi-protein hub binding Imp4, Utp3/Sas10, and ribosomal protein uS7 near the A1 cleavage site.","evidence":"Crystal structure of Imp4-Mpp10 helix at 1.88 Å plus binding assays; cryo-EM of the C. thermophilum 90S at 3.2 Å with atomic model building (building on the 2016 90S cryo-EM)","pmids":["28813493","28967883","27419870"],"confidence":"High","gaps":["Structures are from thermophilic fungi; human-specific features not modeled","Catalytic mechanism of A1/A2 cleavage not assigned to a specific factor"]},{"year":2019,"claim":"Identified Sas10/Utp3 as both a protector that masks the CAPN3 cleavage site on Mpp10 and a delivery factor required for nucleolar localization of the Mpp10-Imp3-Imp4 complex, with Def promoting CAPN3-mediated cleavage.","evidence":"Co-IP, zebrafish knockdown, localization and stability assays","pmids":["30773582"],"confidence":"High","gaps":["Quantitative balance between protection and degradation in vivo not defined","Signals triggering Def-Sas10-Mpp10 complex formation unknown"]},{"year":2022,"claim":"Defined the Def-CAPN3 turnover pathway controlling Mpp10 abundance, mapping the CAPN3 and Def interaction motifs that assemble the nucleolar degradation complex acting on Mpp10.","evidence":"Def-depletion with fractionation and rRNA analysis; truncation/deletion mapping of CAPN3-Def interaction by Co-IP","pmids":["34452850","35878425"],"confidence":"Medium","gaps":["Physiological cue that activates Mpp10 cleavage not defined","Whether turnover is cell-cycle-coupled not directly shown"]},{"year":2024,"claim":"Defined the nucleolar import route, showing UTP3/SAS10 conveys MPP10 to the nucleolus via importin-α, with loss impairing MPP10 localization and A0 cleavage.","evidence":"Systematic localization screen, siRNA knockdown, importin α interaction assay, rRNA processing analysis in human cells","pmids":["39036955"],"confidence":"Medium","gaps":["Direct MPP10 nuclear localization signal not mapped","Single-lab screen"]},{"year":null,"claim":"How M-phase phosphorylation drives MPP10's mitotic redistribution and whether arginine methylation by Hmt1 regulates its processing or trafficking functions remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No identified kinase or functional readout for the M-phase phosphosite","Functional consequence of Hmt1-mediated arginine methylation not established","No direct human disease link characterized in the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[1,3,5,11]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,15]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[0,3,16,20]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[0,3]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1,4,12]}],"complexes":["U3 snoRNP","SSU processome / 90S pre-ribosome","Mpp10-Imp3-Imp4 module","Def-Sas10-Mpp10 complex"],"partners":["IMP3","IMP4","UTP3","US7","U3 SNORNA","UTP11","CAPN3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O00566","full_name":"U3 small nucleolar ribonucleoprotein protein MPP10","aliases":["M phase phosphoprotein 10"],"length_aa":681,"mass_kda":78.9,"function":"Component of the 60-80S U3 small nucleolar ribonucleoprotein (U3 snoRNP). Required for the early cleavages during pre-18S ribosomal RNA processing (PubMed:12655004). 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)","subcellular_location":"Nucleus, nucleolus; Chromosome","url":"https://www.uniprot.org/uniprotkb/O00566/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/MPHOSPH10","classification":"Common Essential","n_dependent_lines":1160,"n_total_lines":1208,"dependency_fraction":0.9602649006622517},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000124383","cell_line_id":"CID001118","localizations":[{"compartment":"nucleolus_gc","grade":3}],"interactors":[{"gene":"UTP3","stoichiometry":10.0},{"gene":"IMP3","stoichiometry":4.0},{"gene":"IMP4","stoichiometry":4.0},{"gene":"CSNK2B","stoichiometry":0.2},{"gene":"DIEXF","stoichiometry":0.2},{"gene":"NPM1","stoichiometry":0.2},{"gene":"RHOA","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001118","total_profiled":1310},"omim":[{"mim_id":"612981","title":"IMP U3 SMALL NUCLEOLAR RIBONUCLEAR PROTEIN 4; IMP4","url":"https://www.omim.org/entry/612981"},{"mim_id":"612980","title":"IMP U3 SMALL NUCLEOLAR RIBONUCLEAR PROTEIN 3; IMP3","url":"https://www.omim.org/entry/612980"},{"mim_id":"605503","title":"M-PHASE PHOSPHOPROTEIN 10; MPHOSPH10","url":"https://www.omim.org/entry/605503"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoli","reliability":"Enhanced"},{"location":"Nucleoli rim","reliability":"Enhanced"},{"location":"Mitotic chromosome","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MPHOSPH10"},"hgnc":{"alias_symbol":["MPP10","MPP10P","CT90","PPP1R106"],"prev_symbol":[]},"alphafold":{"accession":"O00566","domains":[{"cath_id":"-","chopping":"5-97","consensus_level":"high","plddt":82.512,"start":5,"end":97}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O00566","model_url":"https://alphafold.ebi.ac.uk/files/AF-O00566-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O00566-F1-predicted_aligned_error_v6.png","plddt_mean":68.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MPHOSPH10","jax_strain_url":"https://www.jax.org/strain/search?query=MPHOSPH10"},"sequence":{"accession":"O00566","fasta_url":"https://rest.uniprot.org/uniprotkb/O00566.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O00566/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O00566"}},"corpus_meta":[{"pmid":"27419870","id":"PMC_27419870","title":"Architecture of the 90S Pre-ribosome: A Structural View on the Birth of the Eukaryotic Ribosome.","date":"2016","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/27419870","citation_count":181,"is_preprint":false},{"pmid":"8885239","id":"PMC_8885239","title":"Identification of novel M phase phosphoproteins by expression cloning.","date":"1996","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/8885239","citation_count":170,"is_preprint":false},{"pmid":"17515605","id":"PMC_17515605","title":"The 90S preribosome is a multimodular structure that is assembled through a hierarchical mechanism.","date":"2007","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17515605","citation_count":144,"is_preprint":false},{"pmid":"15590835","id":"PMC_15590835","title":"The small-subunit processome is a ribosome assembly intermediate.","date":"2004","source":"Eukaryotic 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In mitosis, it redistributes throughout the cell.\",\n      \"method\": \"Immunofluorescence microscopy and immunoprecipitation with MPM2 antibody from M phase cell lysates\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with immunofluorescence and biochemical validation by immunoprecipitation, single lab but two orthogonal methods\",\n      \"pmids\": [\"8885239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Yeast Mpp10p is a component of the U3 snoRNP: antibodies to purified Mpp10p immunoprecipitate U3 snoRNA from yeast extracts. MPP10 is an essential gene, and depletion of Mpp10p causes accumulation of 23S and 35S pre-rRNA precursors and loss of 18S rRNA and its 20S precursor, demonstrating Mpp10p is required for pre-rRNA cleavage at sites A0, A1, and A2.\",\n      \"method\": \"Co-immunoprecipitation of U3 snoRNA, conditional promoter depletion, Northern blot analysis of pre-rRNA processing, pulse-chase analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus genetic depletion with defined pre-rRNA processing phenotype, replicated across multiple labs subsequently\",\n      \"pmids\": [\"9315638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"C-terminal truncations of Mpp10p separate U3 snoRNP function into two distinct activities: truncated Mpp10p supports cleavage at A0 but not at A1/A2 sites, without affecting Mpp10p-U3 snoRNA association or protein stability, demonstrating the C-terminus is specifically required for A1/A2 processing.\",\n      \"method\": \"Truncation mutagenesis, Northern blot pre-rRNA processing analysis, cold-sensitivity growth assay, co-immunoprecipitation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis with defined processing phenotype replicated and extended by subsequent work\",\n      \"pmids\": [\"9391061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Human MPP10 localizes almost entirely to nucleoli by cell fractionation; by immunofluorescence it co-localizes with nucleolar fibrillarin in interphase but not in coiled bodies. Upon actinomycin D treatment, MPP10 is enriched in fibrillar caps (sites of rRNA processing). In early-to-middle M phase, MPP10 co-localizes with fibrillarin on chromosome surfaces, and at telophase appears in nucleolus-derived bodies and prenucleolar bodies. Immunoprecipitation from cell sonicates shows MPP10 specifically associates with U3 snoRNA but not other box C/D snoRNAs, stable to 400 mM salt, establishing human MPP10 as a U3 snoRNP component.\",\n      \"method\": \"Cell fractionation, immunofluorescence microscopy, immunoprecipitation of snoRNA, actinomycin D treatment\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (fractionation, immunofluorescence, Co-IP with functional specificity controls) in single study with strong controls\",\n      \"pmids\": [\"9450966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Imp3p and Imp4p are two novel U3 snoRNP proteins identified by two-hybrid screening for proteins that physically associate with Mpp10p. Both associate with Mpp10p in vivo and are complexed only with U3 snoRNA. Genetic depletion of either Imp3p or Imp4p causes defects in pre-18S rRNA processing at A0, A1, and A2 sites, and neither is required for U3 snoRNA integrity.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation in vivo, conditional depletion with Northern blot analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two-hybrid identification confirmed by in vivo Co-IP plus genetic depletion phenotype, replicated in subsequent structural and biochemical studies\",\n      \"pmids\": [\"10409734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Association of Mpp10p with the U3 snoRNP requires a conserved sequence element in the U3 snoRNA hinge region (nt 40-72), not the 3' domain sufficient for other U3 snoRNP proteins. This places Mpp10p near the 5' domain that carries out pre-rRNA base-pairing interactions, at the functional center of the U3 snoRNP.\",\n      \"method\": \"U3 snoRNA deletion and truncation analysis by co-immunoprecipitation\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic RNA deletion mapping with Co-IP readout, single lab\",\n      \"pmids\": [\"11421365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Imp3p, Imp4p, and Mpp10p show interdependence for their stability and their association with U3 snoRNA. C-terminal truncations of Mpp10p combined with U3 snoRNA processing-defective mutations produce a more severe A2 cleavage defect than either alone, indicating Mpp10p acts at an additional mechanistic step beyond U3 snoRNA base-pairing maintenance. The last 95 amino acids of yeast Mpp10p are specifically required for growth and pre-rRNA processing at low temperatures, as shown by failed heterologous complementation without this region.\",\n      \"method\": \"Genetic epistasis (double-mutant analysis), heterologous complementation, protein stability assays, co-immunoprecipitation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis analysis combined with complementation and Co-IP, multiple orthogonal approaches in single study\",\n      \"pmids\": [\"12242301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Binding of Mpp10 to the 80S U3 snoRNP processing complex requires sequences within the U3 snoRNA that base pair with the pre-rRNA adjacent to the initial cleavage site. Mutations that inhibit 80S complex formation and/or Mpp10 association cause retention of U3 snoRNA in the dense fibrillar component (DFC) rather than movement to the granular component (GC), indicating Mpp10 association is linked to U3 snoRNA subnucleolar trafficking.\",\n      \"method\": \"U3 snoRNA mutational analysis, immunoprecipitation, subnucleolar fractionation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutational analysis linked to localization phenotype, single lab\",\n      \"pmids\": [\"15367679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Mpp10p-Imp4p protein-protein interaction was tested by reverse two-hybrid screening; mutations in the N-terminal coiled-coil domain of Imp4 confer cold sensitivity, mutations in C-terminus confer temperature sensitivity. Surprisingly, these mutant Imp4 proteins are not measurably defective for Mpp10p interaction within the intact SSU processome, suggesting other complex members maintain this interaction, while still causing pre-rRNA processing defects.\",\n      \"method\": \"Reverse two-hybrid system, co-immunoprecipitation within SSU processome context, pre-rRNA Northern blot analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two-hybrid plus in-complex Co-IP with processing phenotype, single lab\",\n      \"pmids\": [\"14990745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In the 90S preribosome assembly hierarchy, the Mpp10 complex (with Imp3 and Imp4) assembles as a discrete subunit that enters as part of one of two mutually independent assembly routes. This route also involves U3 snoRNP and UTP-B (Pwp2p) subunit binding, which is downstream of the essential t-UTP subunit assembly step.\",\n      \"method\": \"Biochemical fractionation, proteomics, RNA co-immunoprecipitation, bioinformatic assembly modeling\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical fractionation plus proteomic analysis establishing assembly hierarchy, single lab\",\n      \"pmids\": [\"17515605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Human MPP10 is part of a distinct subcomplex within the SSU processome. A novel 50S U3 snoRNP intermediate accumulates when pre-rRNA transcription is blocked or tUTP proteins are depleted; this intermediate lacks the tUTP, bUTP, MPP10, and BMS1/RCL1 subcomplexes, establishing that MPP10 complex recruitment to the SSU processome is dependent on active pre-rRNA transcription and prior tUTP assembly.\",\n      \"method\": \"Sucrose gradient sedimentation, immunoprecipitation, RNAi depletion of tUTP proteins, transcription inhibition\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple depletion conditions plus sedimentation analysis establishing assembly dependence, single lab\",\n      \"pmids\": [\"19332556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The U3 snoRNA hinge region segment VI (forming an 11-bp helix with 5'-ETS) is essential for pre-rRNA processing and cell growth. Compensatory mutations in helix VI restore growth, and specific sequences within segment VI are required for association of Mpp10, Imp4, and Imp3 proteins, placing these proteins at the U3 snoRNA-pre-rRNA interface.\",\n      \"method\": \"Compensatory mutation analysis in vivo, co-immunoprecipitation of Mpp10/Imp4/Imp3 with U3 snoRNA variants\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — compensatory mutation rescue plus Co-IP, single lab\",\n      \"pmids\": [\"21890904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Cryo-EM structure of the Chaetomium thermophilum 90S pre-ribosome identifies the Mpp10-Imp3-Imp4 module as a discrete structural unit within the particle, organized around the 5'-ETS and partially folded 18S rRNA, with the U3 snoRNP positioned centrally.\",\n      \"method\": \"Cryo-EM structural analysis of 90S pre-ribosome\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure of intact complex, identifies Mpp10 complex position directly\",\n      \"pmids\": [\"27419870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Mpp10 is a substrate of the yeast arginine methyltransferase Hmt1, validated by ex vivo methylation assay and MS/MS analysis, establishing Mpp10 as an arginine-methylated protein.\",\n      \"method\": \"Proteome array with anti-methylarginine antibody, ex vivo methylation assay with recombinant Hmt1, MS/MS validation\",\n      \"journal\": \"Proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteome array screen confirmed by ex vivo methylation and MS/MS, single lab but two orthogonal methods\",\n      \"pmids\": [\"26572822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"High-resolution (3.2 Å) cryo-EM structure of the Chaetomium thermophilum 90S preribosome allows atomic model building of the Mpp10 complex. The structure reveals the Mpp10 complex as part of the intertwined assembly factor network that maintains pre-18S RNA domains in an immature state, and identifies the Mpp10 complex in proximity to the unprocessed A1 cleavage site.\",\n      \"method\": \"Cryo-EM at 3.2 Å resolution with atomic model building\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — near-atomic cryo-EM structure with model building, independent replication of 90S structural studies\",\n      \"pmids\": [\"28967883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Crystal structure of Imp4 in complex with a short helical element of Mpp10 resolved at 1.88 Å. Additionally, Mpp10 binds Utp3/Sas10 through two conserved motifs in its N-terminal region, and interacts with ribosomal protein S5/uS7 through a short stretch in an acidic loop region, establishing Mpp10 as a multi-protein interaction platform within the 90S pre-ribosome.\",\n      \"method\": \"X-ray crystallography at 1.88 Å, co-immunoprecipitation, binding assays for novel interactions\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus biochemical validation of multiple novel interactions, multiple orthogonal methods\",\n      \"pmids\": [\"28813493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Sas10/Utp3 stabilizes Mpp10 from Capn3-mediated cleavage by masking the Capn3-recognition site on Mpp10. Def interacts with Sas10 to form the Def-Sas10-Mpp10 complex, which facilitates Capn3-mediated cleavage of Mpp10. Sas10 is required for nucleolar localization of the Mpp10-Imp3-Imp4 complex, establishing Sas10 as both a chaperone/protector and delivery factor for the Mpp10 complex.\",\n      \"method\": \"In vivo protein interaction assays (Co-IP), genetic depletion/knockdown in zebrafish, subcellular localization analysis, protein stability assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, localization, stability assays, in vivo genetics) in zebrafish and cellular models, novel mechanistic pathway established\",\n      \"pmids\": [\"30773582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Mpp10 is a substrate of the nucleolus-localized Def-CAPN3 protein degradation pathway. CAPN3 (Calpain3), recruited to the nucleolus by Def, proteolytically cleaves Mpp10 via a recognition motif on Mpp10. Def depletion leads to accumulation of Mpp10 in the nucleolus and rRNA processing abnormality, establishing Mpp10 turnover as part of cell-cycle control and ribosome biogenesis regulation.\",\n      \"method\": \"Genetic depletion of Def, subcellular fractionation, protein degradation assays, rRNA processing analysis\",\n      \"journal\": \"Journal of genetics and genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic depletion with biochemical and rRNA processing readouts, review/summary paper but cites underlying experimental work\",\n      \"pmids\": [\"34452850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"An 86-amino acid motif (430-515 aa) in human CAPN3 is essential for its interaction with human Def, and the corresponding region is conserved in zebrafish Capn3b. The 2/3 C-terminus of human Def mediates the Def-CAPN3 interaction. This Def-CAPN3 complex mediates degradation of Mpp10 in the nucleolus.\",\n      \"method\": \"Truncation and internal deletion analysis of CAPN3, co-immunoprecipitation of Def-CAPN3 variants\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic deletion mapping by Co-IP, single lab, provides mechanism of Mpp10-relevant degradation complex assembly\",\n      \"pmids\": [\"35878425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"UTP11 binds directly to MPP10 (pre-rRNA processing factor) and is required for 18S rRNA biosynthesis; depletion of UTP11 impedes 18S rRNA production to trigger nucleolar stress.\",\n      \"method\": \"Co-immunoprecipitation/binding assay between UTP11 and MPP10, rRNA processing analysis upon UTP11 depletion\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP/binding claim, single lab, limited mechanistic detail in abstract\",\n      \"pmids\": [\"37087976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"UTP3/SAS10 assists the nucleolar localization of MPP10 (along with UTP25, EMG1, UTP12, and UTP13) through its interaction with nuclear importin α. Knockdown of human UTP3 impairs MPP10 nucleolar localization and cleavage at the pre-rRNA A0-site, establishing a UTP3-dependent nucleolar translocation pathway for MPP10.\",\n      \"method\": \"Systematic localization screen of 50 SSU processome components by fluorescence microscopy, siRNA knockdown, importin α interaction assay, rRNA processing analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic localization screen plus knockdown with functional readout and importin interaction assay, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"39036955\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MPHOSPH10/MPP10 is an essential nucleolar protein and core component of the U3 snoRNP/SSU processome that, together with its direct binding partners Imp3 and Imp4, forms a discrete subcomplex within the 90S pre-ribosome required for endonucleolytic cleavage at the A0, A1, and A2 sites of pre-rRNA to produce mature 18S rRNA; Mpp10 acts as a multi-protein interaction platform (also binding Utp3/Sas10 and ribosomal protein uS7), is delivered to the nucleolus via a UTP3/importin-α-dependent pathway, is subject to arginine methylation by Hmt1 and to proteolytic turnover by the Def-CAPN3 nucleolar degradation pathway (with Sas10 protecting Mpp10 from this cleavage), and undergoes M phase-specific phosphorylation that coincides with its redistribution from nucleoli to chromosome surfaces during mitosis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MPHOSPH10/MPP10 is an essential nucleolar protein that functions as a core component of the U3 snoRNP/SSU processome, where it is required for endonucleolytic cleavage of pre-rRNA at the A0, A1, and A2 sites to generate mature 18S rRNA [#1, #3]. Within the 90S pre-ribosome, Mpp10 forms a discrete structural module with its direct partners Imp3 and Imp4 — interactions identified by two-hybrid screening, confirmed in vivo, and resolved at atomic resolution by crystallography and cryo-EM — that organizes around the 5'-ETS and immature 18S rRNA near the unprocessed A1 cleavage site [#4, #12, #14, #15]. Mpp10 association with the U3 snoRNP depends on a conserved element in the U3 snoRNA hinge region, placing the module at the functional U3 snoRNA–pre-rRNA base-pairing interface, and its C-terminus is specifically required for A1/A2 (but not A0) cleavage, defining a discrete mechanistic role beyond maintenance of U3 base-pairing [#2, #5, #6, #11]. Mpp10 acts as a multi-protein interaction platform, additionally binding Utp3/Sas10 and ribosomal protein uS7, and is delivered to the nucleolus through a UTP3/Sas10–importin-α–dependent route required for A0 cleavage [#15, #16, #20]. Mpp10 abundance is controlled by the nucleolar Def–CAPN3 (Calpain3) degradation pathway, with Sas10 protecting Mpp10 by masking the CAPN3 recognition site, and Mpp10 is also subject to arginine methylation by Hmt1 [#13, #16, #17, #18]. In interphase Mpp10 is nucleolar, but it becomes an M-phase phosphoprotein and redistributes onto chromosome surfaces during mitosis [#0, #3].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established MPHOSPH10 as a nucleolar protein that is cell-cycle regulated, becoming an M-phase phosphoprotein that redistributes during mitosis — the first link between this protein and dynamic nuclear/nucleolar behavior.\",\n      \"evidence\": \"Immunofluorescence and MPM2-antibody immunoprecipitation from M-phase cell lysates\",\n      \"pmids\": [\"8885239\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinase responsible for M-phase phosphorylation not identified\", \"Functional consequence of mitotic redistribution unknown\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Defined the core molecular function: Mpp10 is an essential U3 snoRNP component required for pre-rRNA cleavage at A0, A1, and A2, answering what process the protein serves.\",\n      \"evidence\": \"U3 snoRNA Co-IP, conditional depletion, Northern blot and pulse-chase analysis of pre-rRNA processing in yeast\",\n      \"pmids\": [\"9315638\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve whether Mpp10 acts catalytically or as a scaffold\", \"Partner proteins within the U3 snoRNP not yet defined\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Dissected Mpp10 into separable functional domains by showing the C-terminus is specifically required for A1/A2 but not A0 cleavage, establishing distinct mechanistic steps within the protein.\",\n      \"evidence\": \"C-terminal truncation mutagenesis with pre-rRNA Northern analysis and Co-IP in yeast\",\n      \"pmids\": [\"9391061\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of A1/A2-specific requirement not defined\", \"C-terminal interaction partners unidentified at this stage\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Extended the U3 snoRNP role to human MPP10, with detailed subnucleolar localization and U3-specific snoRNA association, showing functional conservation.\",\n      \"evidence\": \"Cell fractionation, immunofluorescence with fibrillarin, salt-stable snoRNA Co-IP, actinomycin D treatment in human cells\",\n      \"pmids\": [\"9450966\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Human protein interactors beyond U3 snoRNA not defined\", \"Mechanism of mitotic chromosome-surface localization unresolved\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Identified the direct binding partners Imp3 and Imp4 as novel U3 snoRNP proteins, revealing Mpp10 operates as part of a defined protein module.\",\n      \"evidence\": \"Yeast two-hybrid screen, in vivo Co-IP, conditional depletion with Northern analysis\",\n      \"pmids\": [\"10409734\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and architecture of the Mpp10-Imp3-Imp4 module not yet known\", \"Direct interfaces between the three proteins not mapped\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Mapped Mpp10 to the functional center of the U3 snoRNP by showing its association requires the U3 hinge region rather than the 3' domain used by other U3 proteins.\",\n      \"evidence\": \"U3 snoRNA deletion/truncation mapping by Co-IP\",\n      \"pmids\": [\"11421365\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct RNA-protein contact residues not defined\", \"Single-lab RNA mapping\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showed interdependent stability and U3 association of Mpp10, Imp3, and Imp4, and via epistasis that Mpp10 acts at a step beyond U3 base-pairing maintenance.\",\n      \"evidence\": \"Double-mutant epistasis, heterologous complementation, stability assays, Co-IP in yeast\",\n      \"pmids\": [\"12242301\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the additional A2 mechanistic step not defined\", \"Temperature-specific requirement of the terminal 95 residues mechanistically unexplained\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Linked Mpp10 association with the 80S processing complex to U3 snoRNA subnucleolar trafficking from the DFC to the GC.\",\n      \"evidence\": \"U3 snoRNA mutational analysis, immunoprecipitation, subnucleolar fractionation\",\n      \"pmids\": [\"15367679\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causality between Mpp10 binding and trafficking not proven\", \"Single-lab data\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Probed the Mpp10-Imp4 interaction within the intact processome, finding processing-defective Imp4 mutants retain Mpp10 association, implying redundant contacts maintain the module.\",\n      \"evidence\": \"Reverse two-hybrid, in-complex Co-IP, pre-rRNA Northern analysis\",\n      \"pmids\": [\"14990745\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Other complex members maintaining the interaction not identified\", \"Decoupling of processing defect from interaction loss unexplained\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Placed the Mpp10 complex in the SSU processome assembly hierarchy, showing its recruitment depends on active pre-rRNA transcription and prior tUTP assembly in both yeast and human systems.\",\n      \"evidence\": \"Sucrose gradient sedimentation, IP, tUTP RNAi, transcription inhibition (human); biochemical fractionation and assembly modeling (yeast)\",\n      \"pmids\": [\"19332556\", \"17515605\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct recruitment signal/receptor for the Mpp10 complex not identified\", \"Single-lab assembly models\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Refined the RNA contact, showing U3 hinge segment VI (the 11-bp helix with 5'-ETS) is required for Mpp10/Imp3/Imp4 association, positioning the module at the U3-pre-rRNA interface.\",\n      \"evidence\": \"Compensatory mutation rescue in vivo plus Co-IP with U3 variants\",\n      \"pmids\": [\"21890904\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct protein contacts to helix VI not resolved at residue level\", \"Single-lab data\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Resolved the architecture of the Mpp10 module at atomic detail and revealed Mpp10 as a multi-protein hub binding Imp4, Utp3/Sas10, and ribosomal protein uS7 near the A1 cleavage site.\",\n      \"evidence\": \"Crystal structure of Imp4-Mpp10 helix at 1.88 Å plus binding assays; cryo-EM of the C. thermophilum 90S at 3.2 Å with atomic model building (building on the 2016 90S cryo-EM)\",\n      \"pmids\": [\"28813493\", \"28967883\", \"27419870\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structures are from thermophilic fungi; human-specific features not modeled\", \"Catalytic mechanism of A1/A2 cleavage not assigned to a specific factor\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified Sas10/Utp3 as both a protector that masks the CAPN3 cleavage site on Mpp10 and a delivery factor required for nucleolar localization of the Mpp10-Imp3-Imp4 complex, with Def promoting CAPN3-mediated cleavage.\",\n      \"evidence\": \"Co-IP, zebrafish knockdown, localization and stability assays\",\n      \"pmids\": [\"30773582\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative balance between protection and degradation in vivo not defined\", \"Signals triggering Def-Sas10-Mpp10 complex formation unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined the Def-CAPN3 turnover pathway controlling Mpp10 abundance, mapping the CAPN3 and Def interaction motifs that assemble the nucleolar degradation complex acting on Mpp10.\",\n      \"evidence\": \"Def-depletion with fractionation and rRNA analysis; truncation/deletion mapping of CAPN3-Def interaction by Co-IP\",\n      \"pmids\": [\"34452850\", \"35878425\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological cue that activates Mpp10 cleavage not defined\", \"Whether turnover is cell-cycle-coupled not directly shown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined the nucleolar import route, showing UTP3/SAS10 conveys MPP10 to the nucleolus via importin-α, with loss impairing MPP10 localization and A0 cleavage.\",\n      \"evidence\": \"Systematic localization screen, siRNA knockdown, importin α interaction assay, rRNA processing analysis in human cells\",\n      \"pmids\": [\"39036955\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct MPP10 nuclear localization signal not mapped\", \"Single-lab screen\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How M-phase phosphorylation drives MPP10's mitotic redistribution and whether arginine methylation by Hmt1 regulates its processing or trafficking functions remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No identified kinase or functional readout for the M-phase phosphosite\", \"Functional consequence of Hmt1-mediated arginine methylation not established\", \"No direct human disease link characterized in the corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [1, 3, 5, 11]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [0, 3, 16, 20]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1, 4, 12]}\n    ],\n    \"complexes\": [\n      \"U3 snoRNP\",\n      \"SSU processome / 90S pre-ribosome\",\n      \"Mpp10-Imp3-Imp4 module\",\n      \"Def-Sas10-Mpp10 complex\"\n    ],\n    \"partners\": [\n      \"IMP3\",\n      \"IMP4\",\n      \"UTP3\",\n      \"uS7\",\n      \"U3 snoRNA\",\n      \"UTP11\",\n      \"CAPN3\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":6,"faith_pct":100.0}}