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Beyond constitutive heterochromatin, CBX1 nucleates tissue-specific silencing by forming a trimeric complex with PurB and Sp3 that positions nucleosomes and recruits PRC2 to deposit H3K27me3 at cardiomyocyte loci [PMID:35605661]. CBX1 also acts dynamically in the DNA damage response: CK2-mediated phosphorylation of Thr51 disrupts chromodomain folding around H3K9me, mobilizing HP1-beta from chromatin, an event required to initiate H2AX phosphorylation [PMID:18438399]; KAP-1 Ser473 phosphorylation by Chk2 likewise drives HP1-beta mobilization to enable double-strand break repair within heterochromatin [PMID:22715096]. Heterozygous de novo chromodomain variants that reduce heterochromatin binding cause a dominant-negative neurodevelopmental disorder, with mutant HP1-beta sequestering wild-type protein [PMID:37087635]. In cancer contexts CBX1 promotes proliferation, invasion, EMT, and immune evasion through H3K9me3-mediated repression and signaling axes including Wnt/\u03b2-catenin and IGF-1R/AKT/SNAIL [PMID:36310139, PMID:30031230, PMID:38769286].","isoforms":[{"aa_len":239,"canonical_len":185,"chrom":"chr17","conservation":{"phylop_enrichment":0.5633154074480857,"phylop_shared_region_mean":4.952887606355458,"phylop_unique_region_mean":2.7900379000186986},"criteria":{"C1_primate_conservation":true,"C2_mammalian_conservation":true,"C3_phylop_coding_selection":true,"D1_multi_cell_line":true,"D2_initiation_efficiency":true,"D3_mass_spec":true,"L1_localization_change":false,"L2_targeting_change":false,"M1_pathogenic_variant_enrichment":true,"M2_clinical_variant_overlap":false,"P1_structured_extension":true,"P2_shared_structural_change":true,"P3_secondary_structure":true,"S1_domain_change":false,"S2_biophysics":true,"S3_sae":true},"diff_end":54,"diff_space":"isoform","diff_start":0,"differential_sequence":"MRDATAATRLAAFLGATPPGDPTRRASSAAPIPLGLLGAALSSVTLYTRKLAGT","existence_evaluable":6,"existence_score":6,"functional_evaluable":10,"functional_score":6,"isoform_len":239,"kozak_context":"GCCGCTTCAGTGA","localization":{"canonical":"Nucleus","changed":false,"isoform":"Nucleus"},"orf_type":"extended","position":48101392,"reasons":{"C1_primate_conservation":"mean_pident=0.91 (threshold 0.8); 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176 gained + 17 lost features"},"start_codon":"GTG","strand":"-","structure":{"canonical_cif":"CBX1__canonical__185aa.cif","isoform_cif":"CBX1__extended__239aa__chr17-48101392---GTG-ENST00000225603.9.cif","plddt_diffregion_mean":0.7620467841625214,"plddt_isoform_mean":0.8411510412164313,"rmsd_global":4.79154508142336,"tm_score":0.5148368235515309},"tis_id":"chr17:48101392:-:GTG:ENST00000225603.9","transcript_id":"ENST00000225603.9","variants":{"n_pathogenic_in_unique_region":0,"n_total":371,"pathogenic_in_unique_region":[]}},{"aa_len":226,"canonical_len":185,"chrom":"chr17","conservation":{"phylop_enrichment":0.6634841213288729,"phylop_shared_region_mean":4.952887606355458,"phylop_unique_region_mean":3.2861622815434157},"criteria":{"C1_primate_conservation":true,"C2_mammalian_conservation":true,"C3_phylop_coding_selection":true,"D1_multi_cell_line":true,"D2_initiation_efficiency":true,"D3_mass_spec":false,"L1_localization_change":false,"L2_targeting_change":false,"M1_pathogenic_variant_enrichment":true,"M2_clinical_variant_overlap":false,"P1_structured_extension":true,"P2_shared_structural_change":true,"P3_secondary_structure":true,"S1_domain_change":false,"S2_biophysics":true,"S3_sae":true},"diff_end":41,"diff_space":"isoform","diff_start":0,"differential_sequence":"MGATPPGDPTRRASSAAPIPLGLLGAALSSVTLYTRKLAGT","existence_evaluable":6,"existence_score":5,"functional_evaluable":10,"functional_score":6,"isoform_len":226,"kozak_context":"GCTGCCTTCCTGG","localization":{"canonical":"Nucleus","changed":false,"isoform":"Nucleus"},"orf_type":"extended","position":48101353,"reasons":{"C1_primate_conservation":"mean_pident=0.95 (threshold 0.8); 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frac_intact=0.96","C2_mammalian_conservation":"mean_pident=1.00 (threshold 0.5); frac_intact=1.00","C3_phylop_coding_selection":"phylop_unique=4.92 (threshold 2.0); enrichment=0.98 (context)","D1_multi_cell_line":"n_cell_lines=4 (threshold 1)","D2_initiation_efficiency":"max_efficiency=0.577 (threshold 0.01)","D3_mass_spec":"n_validated_unique_peptides=1 (threshold 1)","L1_localization_change":"localization features unchanged (prediction/signals/membrane)","L2_targeting_change":"no targeting change flagged","M1_pathogenic_variant_enrichment":"constraint_enrichment=0.25 (\u22652.0); gnomad_depletion_ratio=1.55 (<0.8)","M2_clinical_variant_overlap":"disease_enrichment_ratio=0.75 (\u22651.0); disease unique=16, shared=73","P1_structured_extension":"plddt_diffregion_mean=0.809 (folded, threshold 0.7)","P2_shared_structural_change":"shared region not confidently folded (min pLDDT 0.58 < 0.7)","P3_secondary_structure":"longest element 5 aa (< 6 aa or below pLDDT 0.7)","S1_domain_change":"n_real_domains_changed_in_diff_region=3","S2_biophysics":"whole-protein |delta| distinct=none (3/3 descriptors evaluable)","S3_sae":"top shared-feature |delta| 4.35 vs threshold 10.0; 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Catalysis proceeds through a thioester at the active-site Cys95, and a dominant-negative C95S mutant blocks both growth and substrate ubiquitination, establishing the catalytic center [PMID:7592826]. CDC34 shows intrinsic kinetic selectivity for processive K48-linked multiubiquitination [PMID:1848239], with chain processivity and linkage specificity governed by a conserved acidic loop and catalytic-core residues that position the donor ubiquitin and lower the pKa of the attacking acceptor lysine [PMID:16360039, PMID:17698585, PMID:21474069, PMID:24129577]. CDC34 functions as the obligate E2 for SCF (Skp1\u2013Cullin/Cdc53\u2013F-box) cullin-RING ligases: Cdc53 scaffolds independent binding sites for CDC34 and Skp1, the RING subunit Hrt1/ROC1 stimulates activity, and the disordered acidic C-terminal tail mediates high-affinity electrostatic binding to the SCF basic canyon while also directly promoting ubiquitin transfer [PMID:9499404, PMID:10385629, PMID:19875449, PMID:25425648]. Through SCF complexes it ubiquitinates cell cycle regulators including Sic1, Swe1/Wee1, and p27Kip1 to license replication and mitotic entry [PMID:9285816, PMID:9716410, PMID:9836638, PMID:15652359], and acts with SCF(\u03b2TrCP) on phospho-I\u03baB\u03b1 in a UbcH5/CDC34 handoff in which a priming E2 attaches the first ubiquitin and CDC34 elongates the K48 chain [PMID:10918611, PMID:20347421]. CDC34 also mediates degradation of additional substrates (ATF5, hICERII\u03b3, B-Myb, c-Ski) and, in the case of Met4, catalyzes a non-proteolytic ubiquitination that inactivates a transcription factor without destroying it [PMID:10373550, PMID:10975521, PMID:10871850, PMID:15122324]. Its activity is tuned by CK2 phosphorylation of both the catalytic domain and acidic tail, which stimulates ubiquitin charging and accelerates cell cycle progression [PMID:17461777, PMID:18418079]. CDC34 is itself a substrate for autoubiquitination and SCF(\u03b2TrCP)-mediated turnover, from which the COP9 signalosome protects it [PMID:8383676, PMID:20378537].","isoforms":[{"aa_len":291,"canonical_len":236,"chrom":"chr19","conservation":{"phylop_enrichment":0.48826534377568925,"phylop_shared_region_mean":4.172068072617272,"phylop_unique_region_mean":2.0370762517320493},"criteria":{"C1_primate_conservation":true,"C2_mammalian_conservation":true,"C3_phylop_coding_selection":true,"D1_multi_cell_line":true,"D2_initiation_efficiency":true,"D3_mass_spec":true,"L1_localization_change":true,"L2_targeting_change":false,"M1_pathogenic_variant_enrichment":true,"M2_clinical_variant_overlap":false,"P1_structured_extension":true,"P2_shared_structural_change":true,"P3_secondary_structure":true,"S1_domain_change":false,"S2_biophysics":false,"S3_sae":false},"diff_end":55,"diff_space":"isoform","diff_start":0,"differential_sequence":"MERSGSPGGGGGAEEEAGGGPGGSPPDGARPGPSRELAVVARPRAAPTPGPSAAA","existence_evaluable":6,"existence_score":6,"functional_evaluable":10,"functional_score":5,"isoform_len":291,"kozak_context":"CCAGAGCTGCTGG","localization":{"canonical":"Cytoplasm|Nucleus","changed":true,"isoform":"Cytoplasm"},"orf_type":"extended","position":531766,"reasons":{"C1_primate_conservation":"mean_pident=0.93 (threshold 0.8); 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Beyond stress sensing, eIF2B\u03b1 carries an ancestral catalytic pocket homologous to sugar-phosphate metabolic enzymes that binds sugar phosphates to allosterically promote holoenzyme assembly and stimulate GEF activity, linking nutrient and glycolytic status to protein synthesis [PMID:26384431, PMID:34103529]. Mutations in EIF2B1 cause vanishing white matter disease \u2014 typically by reducing eIF2B\u03b1 levels and complex stability or by disrupting regulation by phospho-eIF2\u03b1 [PMID:14993275, PMID:26285592] \u2014 and de novo missense mutations clustering on one surface cause permanent neonatal/early-onset diabetes with transient hepatic dysfunction [PMID:31882561]. The decameric eIF2B\u03b1-dependent complex is also required for oncogenic translation in APC-deficient colorectal cancer, defining a therapeutic vulnerability 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It localizes to kinetochores after chromosome condensation and disappears from them by metaphase, and antibody-mediated interference with hsMAD2 abolishes mitotic arrest in response to spindle perturbation, establishing it as functionally required for checkpoint enforcement [PMID:8824189]. Checkpoint activity depends on its association with MAD1: two leucine zipper domains in hsMAD1 (residues 501\u2013522 and 557\u2013571) mediate binding, and a codon-558 Arg\u2192His polymorphism that weakens this interface impairs mitotic arrest [PMID:12042300]. During interphase, both proteins co-localize with nuclear pore complexes rather than with Cdc20 (p55CDC) [PMID:11181178]. Loss of MAD2L1 function\u2014through promoter hypermethylation in hepatocellular carcinoma [PMID:15574775] or a Leu84Met missense variant [PMID:20516147]\u2014produces a defective checkpoint, reduced 4N DNA content, and tetraploidy. MAD2L1 transcription is controlled by multiple upstream inputs, including RUNX1 and the ETV6/RUNX1 fusion acting on RUNX1 sites in its promoter [PMID:20190817], BRCA1 [PMID:33158996], and TEAD4 [PMID:36599972], while its abundance is also set post-transcriptionally by mRNA-stabilizing axes including KIFC1/FXR1 (m6A-dependent) [PMID:39387242] and KAT2A-driven RCC2 lactylation\u2013SERBP1 under high glucose [PMID:40145796]. Beyond mitosis, MAD2L1 participates in oncogenic circuits: it engages a TYK2/STAT3 positive-feedback loop in B-ALL [PMID:36781502] and binds NANOG to promote its nuclear localization and chemoresistance in lung cancer [PMID:40233918].","isoforms":[{"aa_len":226,"canonical_len":205,"chrom":"chr4","conservation":{"phylop_enrichment":-0.08813511445874127,"phylop_shared_region_mean":4.259873621250556,"phylop_unique_region_mean":-0.37544444918869035},"criteria":{"C1_primate_conservation":false,"C2_mammalian_conservation":false,"C3_phylop_coding_selection":false,"D1_multi_cell_line":true,"D2_initiation_efficiency":true,"D3_mass_spec":true,"L1_localization_change":true,"L2_targeting_change":true,"M1_pathogenic_variant_enrichment":true,"M2_clinical_variant_overlap":false,"P1_structured_extension":true,"P2_shared_structural_change":false,"P3_secondary_structure":true,"S1_domain_change":false,"S2_biophysics":false,"S3_sae":true},"diff_end":21,"diff_space":"isoform","diff_start":0,"differential_sequence":"MEPLWLLSAEWKRVLLFVSLA","existence_evaluable":6,"existence_score":3,"functional_evaluable":10,"functional_score":6,"isoform_len":226,"kozak_context":"GAAGTGCTGTTGG","localization":{"canonical":"Cytoplasm","changed":false,"isoform":"Cytoplasm"},"orf_type":"extended","position":120066797,"reasons":{"C1_primate_conservation":"mean_pident=0.74 (threshold 0.8); 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105 gained + 15 lost features"},"start_codon":"TTG","strand":"-","structure":{"canonical_cif":"MAD2L1__canonical__205aa.cif","isoform_cif":"MAD2L1__extended__226aa__chr4-120066797---TTG-ENST00000296509.11.cif","plddt_diffregion_mean":0.7748903234799703,"plddt_isoform_mean":0.923857317561597,"rmsd_global":0.5002356563272076,"tm_score":0.9468431352619711},"tis_id":"chr4:120066797:-:TTG:ENST00000296509.11","transcript_id":"ENST00000296509.11","variants":{"n_pathogenic_in_unique_region":0,"n_total":444,"pathogenic_in_unique_region":[]}},{"aa_len":220,"canonical_len":205,"chrom":"chr4","conservation":{"phylop_enrichment":-0.06677297866361642,"phylop_shared_region_mean":4.259873621250556,"phylop_unique_region_mean":-0.28444445042146577},"criteria":{"C1_primate_conservation":false,"C2_mammalian_conservation":false,"C3_phylop_coding_selection":false,"D1_multi_cell_line":true,"D2_initiation_efficiency":true,"D3_mass_spec":true,"L1_localization_change":true,"L2_targeting_change":true,"M1_pathogenic_variant_enrichment":true,"M2_clinical_variant_overlap":false,"P1_structured_extension":true,"P2_shared_structural_change":true,"P3_secondary_structure":true,"S1_domain_change":false,"S2_biophysics":false,"S3_sae":true},"diff_end":15,"diff_space":"isoform","diff_start":0,"differential_sequence":"MSAEWKRVLLFVSLA","existence_evaluable":6,"existence_score":3,"functional_evaluable":10,"functional_score":7,"isoform_len":220,"kozak_context":"CTGTGGTTGCTGT","localization":{"canonical":"Cytoplasm","changed":false,"isoform":"Cytoplasm"},"orf_type":"extended","position":120066779,"reasons":{"C1_primate_conservation":"mean_pident=0.75 (threshold 0.8); frac_intact=0.88","C2_mammalian_conservation":"mean_pident=0.46 (threshold 0.5); frac_intact=0.20","C3_phylop_coding_selection":"phylop_unique=-0.28 (threshold 2.0); enrichment=-0.07 (context)","D1_multi_cell_line":"n_cell_lines=1 (threshold 1)","D2_initiation_efficiency":"max_efficiency=0.061 (threshold 0.01)","D3_mass_spec":"n_validated_unique_peptides=2 (threshold 1)","L1_localization_change":"localization features changed (prediction/signals/membrane): deeploc_membrane_changed","L2_targeting_change":"changed in: signalp,targetp","M1_pathogenic_variant_enrichment":"constraint_enrichment=51.33 (\u22652.0); gnomad_depletion_ratio=1.84 (<0.8)","M2_clinical_variant_overlap":"disease_enrichment_ratio=0.38 (\u22651.0); disease unique=3, shared=107","P1_structured_extension":"plddt_diffregion_mean=0.856 (folded, threshold 0.7)","P2_shared_structural_change":"shared-region C\u03b1 RMSD 3.39 \u00c5 (\u2265 2.0 \u00c5 threshold), TM-score 0.97, 205 aa, min shared pLDDT 0.94","P3_secondary_structure":"18 aa helix at 3-20 (pLDDT 0.82, thresholds 6 aa / 0.7)","S1_domain_change":"n_real_domains_changed_in_diff_region=0","S2_biophysics":"whole-protein |delta| distinct=none (3/3 descriptors evaluable)","S3_sae":"top shared-feature |delta| 12.81 vs threshold 10.0; 67 gained + 12 lost features"},"start_codon":"CTG","strand":"-","structure":{"canonical_cif":"MAD2L1__canonical__205aa.cif","isoform_cif":"MAD2L1__extended__220aa__chr4-120066779---CTG-ENST00000296509.11.cif","plddt_diffregion_mean":0.8561360478401184,"plddt_isoform_mean":0.9353509053587914,"rmsd_global":0.7700522816454004,"tm_score":0.9347823776058651},"tis_id":"chr4:120066779:-:CTG:ENST00000296509.11","transcript_id":"ENST00000296509.11","variants":{"n_pathogenic_in_unique_region":0,"n_total":431,"pathogenic_in_unique_region":[]}},{"aa_len":175,"canonical_len":205,"chrom":"chr4","conservation":{"phylop_enrichment":0.9495763827224901,"phylop_shared_region_mean":4.301062661820099,"phylop_unique_region_mean":4.0841875242738945},"criteria":{"C1_primate_conservation":true,"C2_mammalian_conservation":true,"C3_phylop_coding_selection":true,"D1_multi_cell_line":true,"D2_initiation_efficiency":true,"D3_mass_spec":false,"L1_localization_change":false,"L2_targeting_change":false,"M1_pathogenic_variant_enrichment":false,"M2_clinical_variant_overlap":true,"P1_structured_extension":true,"P2_shared_structural_change":null,"P3_secondary_structure":true,"S1_domain_change":false,"S2_biophysics":false,"S3_sae":false},"diff_end":31,"diff_space":"canonical","diff_start":0,"differential_sequence":"MALQLSREQGITLRGSAEIVAEFFSFGINSI","existence_evaluable":6,"existence_score":5,"functional_evaluable":9,"functional_score":3,"isoform_len":175,"kozak_context":"ATCAACAGCATTT","localization":{"canonical":"Cytoplasm","changed":false,"isoform":"Cytoplasm"},"orf_type":"truncated","position":120065801,"reasons":{"C1_primate_conservation":"mean_pident=0.99 (threshold 0.8); frac_intact=1.00","C2_mammalian_conservation":"mean_pident=0.93 (threshold 0.5); frac_intact=0.80","C3_phylop_coding_selection":"phylop_unique=4.08 (threshold 2.0); enrichment=0.95 (context)","D1_multi_cell_line":"n_cell_lines=1 (threshold 1)","D2_initiation_efficiency":"max_efficiency=0.043 (threshold 0.01)","D3_mass_spec":"n_validated_unique_peptides=0 (threshold 1)","L1_localization_change":"localization features unchanged (prediction/signals/membrane)","L2_targeting_change":"no targeting change flagged","M1_pathogenic_variant_enrichment":"constraint_enrichment=0.34 (\u22652.0); gnomad_depletion_ratio=1.70 (<0.8)","M2_clinical_variant_overlap":"disease_enrichment_ratio=1.42 (\u22651.0); disease unique=21, shared=86","P1_structured_extension":"plddt_diffregion_mean=0.896 (folded, threshold 0.7)","P2_shared_structural_change":"shared region not confidently folded (min pLDDT 0.64 < 0.7)","P3_secondary_structure":"23 aa helix at 13-35 (pLDDT 0.96, thresholds 6 aa / 0.7)","S1_domain_change":"n_real_domains_changed_in_diff_region=0","S2_biophysics":"whole-protein |delta| distinct=none (3/3 descriptors evaluable)","S3_sae":"top shared-feature |delta| 8.00 vs threshold 10.0; 12 gained + 68 lost features"},"start_codon":"ATT","strand":"-","structure":{"canonical_cif":"MAD2L1__canonical__205aa.cif","isoform_cif":"MAD2L1__truncated__175aa__chr4-120065801---ATT-ENST00000296509.11.cif","plddt_diffregion_mean":0.8963183529915348,"plddt_isoform_mean":0.6368974767412459,"rmsd_global":2.396310204698059,"tm_score":0.8219247639891045},"tis_id":"chr4:120065801:-:ATT:ENST00000296509.11","transcript_id":"ENST00000296509.11","variants":{"n_pathogenic_in_unique_region":0,"n_total":390,"pathogenic_in_unique_region":[{"aa_alt":"E","aa_ref":"E","allele_frequency":null,"alt":"C","chrom":"chr4","clinical_significance":"Likely benign","consequence":"synonymous_variant","genomic_pos":120066681,"hgvsp":"p.Glu18=","in_isoform":false,"in_isoform_shared":false,"in_isoform_unique":true,"isoform_aa_alt":null,"isoform_aa_ref":null,"isoform_consequence":"intronic","isoform_protein_pos":null,"metadata":{"consequence_source":"single nucleotide variant","cosmic_sample_count":null,"hgvsc":null,"hgvsp_canonical_hint":17.0,"mutation_aa":null,"mutation_cds":null,"protein_position_vep":null,"review_stars":1.0,"review_status":"criteria provided, single submitter","rs_id":1166219164.0,"somatic_status":null,"title":"NM_002358.4(MAD2L1):c.54A>G (p.Glu18=)"},"protein_pos":17.0,"ref":"T","source":"ClinVar","variant_id":"ClinVar:2655056"},{"aa_alt":"L","aa_ref":"L","allele_frequency":null,"alt":"A","chrom":"chr4","clinical_significance":"Likely benign","consequence":"synonymous_variant","genomic_pos":120066698,"hgvsp":"p.Leu13=","in_isoform":false,"in_isoform_shared":false,"in_isoform_unique":true,"isoform_aa_alt":null,"isoform_aa_ref":null,"isoform_consequence":"intronic","isoform_protein_pos":null,"metadata":{"consequence_source":"single nucleotide variant","cosmic_sample_count":null,"hgvsc":null,"hgvsp_canonical_hint":12.0,"mutation_aa":null,"mutation_cds":null,"protein_position_vep":null,"review_stars":1.0,"review_status":"criteria provided, single submitter","rs_id":1174188210.0,"somatic_status":null,"title":"NM_002358.4(MAD2L1):c.37C>T (p.Leu13=)"},"protein_pos":12.0,"ref":"G","source":"ClinVar","variant_id":"ClinVar:2655057"},{"aa_alt":"G","aa_ref":"G","allele_frequency":null,"alt":"G","chrom":"chr4","clinical_significance":"Likely benign","consequence":"synonymous_variant","genomic_pos":120066705,"hgvsp":"p.Gly10=","in_isoform":false,"in_isoform_shared":false,"in_isoform_unique":true,"isoform_aa_alt":null,"isoform_aa_ref":null,"isoform_consequence":"intronic","isoform_protein_pos":null,"metadata":{"consequence_source":"single nucleotide variant","cosmic_sample_count":null,"hgvsc":null,"hgvsp_canonical_hint":9.0,"mutation_aa":null,"mutation_cds":null,"protein_position_vep":null,"review_stars":1.0,"review_status":"criteria provided, single submitter","rs_id":1347231065.0,"somatic_status":null,"title":"NM_002358.4(MAD2L1):c.30A>C (p.Gly10=)"},"protein_pos":9.0,"ref":"T","source":"ClinVar","variant_id":"ClinVar:2655058"},{"aa_alt":"Q","aa_ref":"Q","allele_frequency":null,"alt":"T","chrom":"chr4","clinical_significance":"Likely benign","consequence":"synonymous_variant","genomic_pos":120066708,"hgvsp":"p.Gln9=","in_isoform":false,"in_isoform_shared":false,"in_isoform_unique":true,"isoform_aa_alt":null,"isoform_aa_ref":null,"isoform_consequence":"intronic","isoform_protein_pos":null,"metadata":{"consequence_source":"single nucleotide variant","cosmic_sample_count":null,"hgvsc":null,"hgvsp_canonical_hint":8.0,"mutation_aa":null,"mutation_cds":null,"protein_position_vep":null,"review_stars":1.0,"review_status":"criteria provided, single submitter","rs_id":1431562411.0,"somatic_status":null,"title":"NM_002358.4(MAD2L1):c.27G>A (p.Gln9=)"},"protein_pos":8.0,"ref":"C","source":"ClinVar","variant_id":"ClinVar:2655059"}]}}],"keywords":["molecular function regulator activity","molecular transducer activity","Cell Cycle"],"llm":null,"location":"nucleus; nuclear envelope","name":"MAD2L1","uniprot_id":"Q13257","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13257/entry"},"SRSF2":{"canonical_cif":"SRSF2__canonical__221aa.cif","canonical_len":221,"function":"SRSF2 (SC35) is an essential SR-family pre-mRNA splicing factor that recognizes degenerate exonic splicing enhancers through its RRM and promotes spliceosome assembly, splice-site selection, and exon inclusion across many tissue-specific programs [PMID:1373910, PMID:1454802]. It was originally isolated as a factor required for the first step of splicing and for spliceosome assembly, reconstituting splicing activity in S100 and immunodepleted extracts where it favors proximal splice sites in antagonism with hnRNP A1 [PMID:1373910, PMID:1454802], and it can substitute for U2AF65 to recruit U2 snRNP in a substrate-specific, U1 snRNP-dependent manner [PMID:8990173]. Sequence-specificity studies and solution NMR structures of the RRM define a high-affinity 5'-SSNG-3' consensus, with the protein binding 5'-UCCAGU-3' and 5'-UGGAGU-3' equally by flipping central C or G bases between anti and syn conformations and with the elongated L3 loop essential for RNA contact [PMID:10629063, PMID:22002536, PMID:22140111]; the RRM also serves as a reader of m5C-modified mRNA, with NSUN2-deposited m5C enhancing SRSF2 binding [PMID:38065062]. Beyond splicing, SRSF2 facilitates transcriptional elongation by promoting P-TEFb recruitment and CTD Ser2 phosphorylation [PMID:18641664] and autoregulates its own expression through alternative splicing of its terminal exon coupled to mRNA surveillance [PMID:11285241, PMID:19965769]. Its activity is tuned by post-translational control, including Tip60-mediated K52 acetylation that drives proteasomal degradation and HDAC6/SRPK opposition [PMID:21157427]. Genetically, SRSF2 is required for T cell maturation, cardiac and hepatic homeostasis, and myogenesis, regulating defined targets such as CD45, RyR2, and stress-death pathway genes [PMID:11239462, PMID:14963485, PMID:27022105, PMID:35460187]. Recurrent Pro95 hot-spot mutations (e.g., P95H) cause myelodysplastic/myeloproliferative neoplasms by shifting RNA-binding specificity toward UCCAG over UGGAG motifs, mis-splicing hematopoietic regulators including EZH2 and HNRNPA2B1, enhancing EJC-dependent nonsense-mediated decay, impairing m5C reading, and disrupting mitochondrial mRNA splicing such that PINK1-mediated mitophagy becomes essential for mutant-cell survival [PMID:25965569, PMID:26261309, PMID:29858584, PMID:32001512, PMID:38065062, PMID:38713535].","isoforms":[{"aa_len":256,"canonical_len":221,"chrom":"chr17","conservation":{"phylop_enrichment":0.29567475196532267,"phylop_shared_region_mean":4.300886291248036,"phylop_unique_region_mean":1.2716634873958195},"criteria":{"C1_primate_conservation":true,"C2_mammalian_conservation":true,"C3_phylop_coding_selection":false,"D1_multi_cell_line":true,"D2_initiation_efficiency":true,"D3_mass_spec":true,"L1_localization_change":false,"L2_targeting_change":false,"M1_pathogenic_variant_enrichment":true,"M2_clinical_variant_overlap":false,"P1_structured_extension":true,"P2_shared_structural_change":true,"P3_secondary_structure":true,"S1_domain_change":false,"S2_biophysics":false,"S3_sae":true},"diff_end":35,"diff_space":"isoform","diff_start":0,"differential_sequence":"MSPRGRQLPERRGVAPPRAEEAGASSRGSGPPLRA","existence_evaluable":6,"existence_score":5,"functional_evaluable":10,"functional_score":5,"isoform_len":256,"kozak_context":"CCTTTCCCAGTGT","localization":{"canonical":"Nucleus","changed":false,"isoform":"Nucleus"},"orf_type":"extended","position":76737265,"reasons":{"C1_primate_conservation":"mean_pident=0.84 (threshold 0.8); frac_intact=0.83","C2_mammalian_conservation":"mean_pident=0.62 (threshold 0.5); frac_intact=0.24","C3_phylop_coding_selection":"phylop_unique=1.27 (threshold 2.0); enrichment=0.30 (context)","D1_multi_cell_line":"n_cell_lines=4 (threshold 1)","D2_initiation_efficiency":"max_efficiency=0.804 (threshold 0.01)","D3_mass_spec":"n_validated_unique_peptides=1 (threshold 1)","L1_localization_change":"localization features unchanged (prediction/signals/membrane)","L2_targeting_change":"no targeting change flagged","M1_pathogenic_variant_enrichment":"constraint_enrichment=234.49 (\u22652.0); gnomad_depletion_ratio=2.05 (<0.8)","M2_clinical_variant_overlap":"disease_enrichment_ratio=0.06 (\u22651.0); disease unique=2, shared=222","P1_structured_extension":"plddt_diffregion_mean=0.803 (folded, threshold 0.7)","P2_shared_structural_change":"shared-region C\u03b1 RMSD 19.81 \u00c5 (\u2265 2.0 \u00c5 threshold), TM-score 0.45, 221 aa, min shared pLDDT 0.79","P3_secondary_structure":"13 aa strand at 2-14 (pLDDT 0.81, thresholds 6 aa / 0.7)","S1_domain_change":"n_real_domains_changed_in_diff_region=0","S2_biophysics":"whole-protein |delta| distinct=none (3/3 descriptors evaluable)","S3_sae":"top shared-feature |delta| 10.14 vs threshold 10.0; 105 gained + 17 lost features"},"start_codon":"GTG","strand":"-","structure":{"canonical_cif":"SRSF2__canonical__221aa.cif","isoform_cif":"SRSF2__extended__256aa__chr17-76737265---GTG-ENST00000585202.5.cif","plddt_diffregion_mean":0.8032378792762757,"plddt_isoform_mean":0.7875303186010569,"rmsd_global":3.193478994052041,"tm_score":0.4198569185978155},"tis_id":"chr17:76737265:-:GTG:ENST00000585202.5","transcript_id":"ENST00000585202.5","variants":{"n_pathogenic_in_unique_region":0,"n_total":714,"pathogenic_in_unique_region":[]}}],"keywords":["RNA binding","transcription regulator activity","catalytic activity, acting on RNA","Metabolism of RNA","Gene expression (Transcription)","Disease"],"llm":null,"location":"nucleus; nucleoplasm","name":"SRSF2","uniprot_id":"Q01130","uniprot_url":"https://www.uniprot.org/uniprotkb/Q01130/entry"},"TRIP13":{"canonical_cif":"TRIP13__canonical__432aa.cif","canonical_len":432,"function":"TRIP13 is a hexameric AAA+ ATPase that functions as a universal remodeler of HORMA-domain proteins, coupling ATP-driven translocation to conformational conversion of its clients from a signaling-active 'closed' state to an inactive 'open' state [PMID:25918846, PMID:29973720]. Working with the adapter p31(comet), TRIP13 engages the disordered N-terminus of closed-conformation MAD2 through its axial pore loops and locally unfolds the MAD2 C-terminal \u03b1A helix, dissociating MAD2 from its partners; this remodeling disassembles the mitotic checkpoint complex and silences the spindle assembly checkpoint to permit anaphase onset, a reaction reconstituted from purified components and visualized by crystal and cryo-EM structures of the remodeling complex [PMID:25918846, PMID:25092294, PMID:29208896, PMID:29973720]. The same N-terminal engagement mechanism is conserved across HORMA clients: TRIP13 removes meiotic HORMAD1/HORMAD2 from synapsed chromosome axes and is required for synaptonemal complex formation, recombination progression after strand invasion, and crossover control during mouse meiosis [PMID:19851446, PMID:17696610, PMID:20711356, PMID:28659378, PMID:39207914]. Beyond mitosis and meiosis, TRIP13 disassembles the REV7(MAD2L2)-Shieldin and REV7-REV3/Pol-\u03b6 complexes by the analogous closed-to-open conversion of REV7, shifting DNA repair toward homologous recombination and away from error-prone end-joining and translesion synthesis [PMID:31915374, PMID:33597306]. Its catalytic activity additionally supports HR-mediated tolerance of oncogene-induced replication stress in KRAS-mutant cells [PMID:40115747]. Biallelic loss-of-function TRIP13 mutations impair the spindle assembly checkpoint and cause chromosome missegregation in patient cells, with rescue upon TRIP13 reintroduction [PMID:28553959]. In cancer contexts, TRIP13 acts through additional partners\u2014enhancing USP7-substrate deubiquitination to stabilize oncoproteins [PMID:34061780], and stabilizing or activating partners including HAT1, DDX21, ACTN4, and YWHAE to drive proliferative signaling [PMID:31533816, PMID:41535263, PMID:39187490, PMID:38012658]; it is also subject to EGFR-mediated Y56 phosphorylation that enhances NHEJ and radioresistance [PMID:34111559].","isoforms":[{"aa_len":456,"canonical_len":432,"chrom":"chr5","conservation":{"phylop_enrichment":0.07726678377702384,"phylop_shared_region_mean":3.0763827178810885,"phylop_unique_region_mean":0.23770219827789102},"criteria":{"C1_primate_conservation":false,"C2_mammalian_conservation":true,"C3_phylop_coding_selection":false,"D1_multi_cell_line":true,"D2_initiation_efficiency":true,"D3_mass_spec":true,"L1_localization_change":true,"L2_targeting_change":false,"M1_pathogenic_variant_enrichment":true,"M2_clinical_variant_overlap":false,"P1_structured_extension":true,"P2_shared_structural_change":false,"P3_secondary_structure":true,"S1_domain_change":false,"S2_biophysics":false,"S3_sae":false},"diff_end":24,"diff_space":"isoform","diff_start":0,"differential_sequence":"MAATLGVRWRRPRPGWVPTALGGA","existence_evaluable":6,"existence_score":4,"functional_evaluable":10,"functional_score":4,"isoform_len":456,"kozak_context":"GCAGCGGCTGTGG","localization":{"canonical":"Cytoplasm|Nucleus","changed":true,"isoform":"Nucleus"},"orf_type":"extended","position":892926,"reasons":{"C1_primate_conservation":"mean_pident=0.78 (threshold 0.8); frac_intact=0.86","C2_mammalian_conservation":"mean_pident=0.54 (threshold 0.5); frac_intact=0.21","C3_phylop_coding_selection":"phylop_unique=0.24 (threshold 2.0); enrichment=0.08 (context)","D1_multi_cell_line":"n_cell_lines=4 (threshold 1)","D2_initiation_efficiency":"max_efficiency=0.048 (threshold 0.01)","D3_mass_spec":"n_validated_unique_peptides=1 (threshold 1)","L1_localization_change":"localization features changed (prediction/signals/membrane): deeploc_prediction_changed","L2_targeting_change":"no targeting change flagged","M1_pathogenic_variant_enrichment":"constraint_enrichment=5.99 (\u22652.0); gnomad_depletion_ratio=2.57 (<0.8)","M2_clinical_variant_overlap":"disease_enrichment_ratio=0.11 (\u22651.0); disease unique=2, shared=318","P1_structured_extension":"plddt_diffregion_mean=0.735 (folded, threshold 0.7)","P2_shared_structural_change":"shared-region C\u03b1 RMSD 0.77 \u00c5 (< 2.0 \u00c5 threshold), TM-score 0.99, 432 aa, min shared pLDDT 0.92","P3_secondary_structure":"6 aa strand at 7-12 (pLDDT 0.78, thresholds 6 aa / 0.7)","S1_domain_change":"n_real_domains_changed_in_diff_region=0","S2_biophysics":"whole-protein |delta| distinct=none (3/3 descriptors evaluable)","S3_sae":"top shared-feature |delta| 7.70 vs threshold 10.0; 177 gained + 46 lost features"},"start_codon":"GTG","strand":"+","structure":{"canonical_cif":"TRIP13__canonical__432aa.cif","isoform_cif":"TRIP13__extended__456aa__chr5-892926---GTG-ENST00000166345.8.cif","plddt_diffregion_mean":0.7348132207989693,"plddt_isoform_mean":0.9139449100353216,"rmsd_global":0.770185273682563,"tm_score":0.9644766070499231},"tis_id":"chr5:892926:+:GTG:ENST00000166345.8","transcript_id":"ENST00000166345.8","variants":{"n_pathogenic_in_unique_region":0,"n_total":1040,"pathogenic_in_unique_region":[]}}],"keywords":["ATP-dependent activity","catalytic activity, acting on a protein","molecular function regulator activity","hydrolase activity","Cell Cycle","DNA Repair","Reproduction","Metabolism of proteins","Signal Transduction"],"llm":null,"location":"microtubule organizing center; chromosome; nucleus; cytosol","name":"TRIP13","uniprot_id":"Q15645","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15645/entry"},"TRNT1":{"canonical_cif":"TRNT1__canonical__434aa.cif","canonical_len":434,"function":"TRNT1 encodes the CCA-adding enzyme essential for maturation of both cytoplasmic and mitochondrial tRNAs, and biallelic loss-of-function mutations cause the multisystem SIFD syndrome [PMID:25193871]. The enzyme adds the CCA trinucleotide to tRNA 3' ends in both compartments; in patient cells with reduced TRNT1, CCA addition is selectively impaired for the non-canonical mitochondrial tRNA(Ser(AGY)), and complete knockdown renders this tRNA undetectable and abolishes synthesis of mitochondrial polypeptides containing Ser(AGY) codons while sparing those that lack them [PMID:25652405]. Impaired CCA addition extends to other mt-tRNAs including tRNA(Cys), tRNA(LeuUUR) and tRNA(His) [PMID:27370603], and the downstream consequence is reduced abundance of select OXPHOS complex proteins with decreased basal and maximal cellular respiration, the disease mutations leaving TRNT1 subcellular localization intact [PMID:27317422]. Beyond defective mitochondrial translation, TRNT1 deficiency triggers a broader stress program: angiogenin-dependent tRNA fragmentation, eIF2\u03b1 phosphorylation, elevated reactive oxygen species, and altered translation of specific proteins [PMID:37239403], together with autophagy defects (aberrant LC3-II accumulation) in patient-derived retinal organoids [PMID:28390992] and an augmented ER stress response in activated T cells [PMID:30758723]. Loss-of-function is causal in vivo: morpholino suppression of trnt1 in zebrafish recapitulates anemia, sensory organ defects, and dose-dependent visual dysfunction that is rescued by human TRNT1 RNA [PMID:26494905].","isoforms":[{"aa_len":405,"canonical_len":434,"chrom":"chr3","conservation":{"phylop_enrichment":0.4492652837325692,"phylop_shared_region_mean":3.371143082261295,"phylop_unique_region_mean":1.5145375533552086},"criteria":{"C1_primate_conservation":true,"C2_mammalian_conservation":true,"C3_phylop_coding_selection":false,"D1_multi_cell_line":true,"D2_initiation_efficiency":true,"D3_mass_spec":false,"L1_localization_change":true,"L2_targeting_change":true,"M1_pathogenic_variant_enrichment":true,"M2_clinical_variant_overlap":true,"P1_structured_extension":true,"P2_shared_structural_change":false,"P3_secondary_structure":true,"S1_domain_change":false,"S2_biophysics":false,"S3_sae":true},"diff_end":29,"diff_space":"canonical","diff_start":0,"differential_sequence":"MLRCLYHWHRPVLNRRWSRLCLPKQYLFT","existence_evaluable":6,"existence_score":4,"functional_evaluable":10,"functional_score":7,"isoform_len":405,"kozak_context":"CTATTCACAATGA","localization":{"canonical":"Mitochondrion","changed":true,"isoform":"Cytoplasm|Nucleus"},"orf_type":"truncated","position":3129127,"reasons":{"C1_primate_conservation":"mean_pident=0.84 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After charging with ubiquitin via E1, it transfers ubiquitin to substrate lysines in cooperation with a broad array of RING and HECT E3 ligases, including E6AP for p53 [PMID:7724550], Mdm2 for p53 [PMID:15280377], the APC11 RING for securin and cyclin B [PMID:10922056], SCF complexes for I\u03baB\u03b1 and the transcription factor GCM1 [PMID:10918611, PMID:18703417], and c-Cbl for EGFR [PMID:18508924]. Its catalytic mechanism is governed by conformational control: RING-domain binding (e.g., cIAP1, MUL1) and non-covalent ubiquitin engagement at the E2 backside surface stabilize a closed UbcH5B~Ub conformation that primes the thioester for transfer [PMID:30523153, PMID:35048531], and self-assembly of the UbcH5b~Ub conjugate into a spiral via backside interactions provides multiple active sites for processive ubiquitination [PMID:20152160]. UBE2D2 supports diverse cellular processes, contributing to PINK1-Parkin-dependent mitophagy through ubiquitination of mitochondrial proteins [PMID:24906799], to VEGFR2 trafficking and angiogenic signaling in endothelial cells [PMID:37226882], and\u2014via genetic analysis in yeast\u2014it performs an essential HECT-E3-dependent function while acting as a monoubiquitinating E2 in RING-E3 pathways [PMID:21357418].","isoforms":[{"aa_len":178,"canonical_len":147,"chrom":"chr5","conservation":{"phylop_enrichment":0.6631883662365454,"phylop_shared_region_mean":5.76654904103186,"phylop_unique_region_mean":3.824308237344837},"criteria":{"C1_primate_conservation":true,"C2_mammalian_conservation":true,"C3_phylop_coding_selection":true,"D1_multi_cell_line":true,"D2_initiation_efficiency":true,"D3_mass_spec":false,"L1_localization_change":true,"L2_targeting_change":false,"M1_pathogenic_variant_enrichment":true,"M2_clinical_variant_overlap":false,"P1_structured_extension":true,"P2_shared_structural_change":false,"P3_secondary_structure":false,"S1_domain_change":false,"S2_biophysics":true,"S3_sae":false},"diff_end":31,"diff_space":"isoform","diff_start":0,"differential_sequence":"MAEAASGSLAPSPSLPRPRPRPGGRRHPPPT","existence_evaluable":6,"existence_score":5,"functional_evaluable":10,"functional_score":4,"isoform_len":178,"kozak_context":"CCGACCGAGATCG","localization":{"canonical":"Cytoplasm|Nucleus","changed":false,"isoform":"Cytoplasm|Nucleus"},"orf_type":"extended","position":139561698,"reasons":{"C1_primate_conservation":"mean_pident=0.97 (threshold 0.8); frac_intact=0.87","C2_mammalian_conservation":"mean_pident=0.82 (threshold 0.5); frac_intact=0.44","C3_phylop_coding_selection":"phylop_unique=3.82 (threshold 2.0); enrichment=0.66 (context)","D1_multi_cell_line":"n_cell_lines=5 (threshold 1)","D2_initiation_efficiency":"max_efficiency=0.172 (threshold 0.01)","D3_mass_spec":"n_validated_unique_peptides=0 (threshold 1)","L1_localization_change":"localization features changed (prediction/signals/membrane): deeploc_membrane_changed","L2_targeting_change":"no targeting change flagged","M1_pathogenic_variant_enrichment":"constraint_enrichment=110.90 (\u22652.0); gnomad_depletion_ratio=5.92 (<0.8)","M2_clinical_variant_overlap":"disease_enrichment_ratio=0.25 (\u22651.0); disease unique=3, shared=58","P1_structured_extension":"plddt_diffregion_mean=0.909 (folded, threshold 0.7)","P2_shared_structural_change":"shared-region C\u03b1 RMSD 0.23 \u00c5 (< 2.0 \u00c5 threshold), TM-score 1.00, 147 aa, min shared pLDDT 0.89","P3_secondary_structure":"longest element 5 aa (< 6 aa or below pLDDT 0.7)","S1_domain_change":"n_real_domains_changed_in_diff_region=0","S2_biophysics":"whole-protein |delta| distinct=disorder (3/3 descriptors evaluable)","S3_sae":"top shared-feature |delta| 6.04 vs threshold 10.0; 153 gained + 34 lost features"},"start_codon":"ATC","strand":"+","structure":{"canonical_cif":"UBE2D2__canonical__147aa.cif","isoform_cif":"UBE2D2__extended__178aa__chr5-139561698---ATC-ENST00000398733.8.cif","plddt_diffregion_mean":0.9087510974176468,"plddt_isoform_mean":0.9605232634571161,"rmsd_global":0.23057243330245272,"tm_score":0.9107880770517056},"tis_id":"chr5:139561698:+:ATC:ENST00000398733.8","transcript_id":"ENST00000398733.8","variants":{"n_pathogenic_in_unique_region":0,"n_total":306,"pathogenic_in_unique_region":[]}}],"keywords":["catalytic activity, acting on a protein","transferase activity","protein tag activity","Metabolism of proteins","Cell Cycle","Autophagy","Signal Transduction"],"llm":null,"location":"cytosol; endosome","name":"UBE2D2","uniprot_id":"P62837","uniprot_url":"https://www.uniprot.org/uniprotkb/P62837/entry"},"UBE2M":{"canonical_cif":"UBE2M__canonical__183aa.cif","canonical_len":183,"function":"UBE2M (hUbc12/UBC12) is the primary E2 NEDD8-conjugating enzyme that drives neddylation of cullin-RING E3 ligases, coupling protein modification to cell-cycle, DNA-repair, immune, and metabolic programs [PMID:10828074, PMID:25025768]. It is charged with activated NEDD8 by the NEDD8 E1 (APPBP1-UBA3), which recruits UBE2M through a ubiquitin-like binding domain that engages the E2 catalytic core in a manner overlapping the E3-binding surface, and transfer to substrates requires the essential active-site cysteine C111 [PMID:15694336, PMID:10828074]. Substrate specificity is sharpened by the co-E3 DCN1, which binds a 12-residue N-terminal UBE2M peptide; this interaction is selectively required for neddylation of cullin 3 (and cullin 1), and disrupting it with peptidomimetic or small-molecule inhibitors converts these cullins to inactive un-neddylated forms [PMID:29074978, PMID:29438612, PMID:42067003]. Through cullin neddylation UBE2M activates CRLs that turn over key substrates including CDT1, p21, p27, Wee1, and Claspin, so its loss stabilizes these factors, blocks cell-cycle progression, impairs RAD51-dependent homologous recombination, and elevates DNA damage [PMID:25025768, PMID:31208947]. Beyond cullins, UBE2M directly neddylates a growing set of non-cullin substrates \u2014 TRIM21, MKK7, EGFR, VEGFR2, NAA10, and USP39 \u2014 typically stabilizing them by antagonizing their ubiquitin-mediated degradation, thereby tuning inflammatory, MAPK/JNK, receptor-tyrosine-kinase, and translation pathways [PMID:37343564, PMID:41361309, PMID:41857595, PMID:42209461, PMID:41680469, PMID:42111190]. UBE2M can also act as a ubiquitylation E2: under stress it partners with Parkin-DJ-1 to degrade the sister neddylation E2 UBE2F, inactivating CRL5 [PMID:29932898]. Its own activity and abundance are controlled by PRMT1-mediated arginine methylation at R169, by TRIM21-mediated ubiquitination in a STAT1/IFN-I negative-feedback loop, and by a primate-specific PINK1 interaction that sustains UBE2M protein levels [PMID:36662617, PMID:41298302, PMID:40744915].","isoforms":[{"aa_len":248,"canonical_len":183,"chrom":"chr19","conservation":{"phylop_enrichment":0.7128926565065291,"phylop_shared_region_mean":5.625607938995368,"phylop_unique_region_mean":4.010454588094628},"criteria":{"C1_primate_conservation":true,"C2_mammalian_conservation":true,"C3_phylop_coding_selection":true,"D1_multi_cell_line":true,"D2_initiation_efficiency":true,"D3_mass_spec":true,"L1_localization_change":false,"L2_targeting_change":false,"M1_pathogenic_variant_enrichment":true,"M2_clinical_variant_overlap":false,"P1_structured_extension":true,"P2_shared_structural_change":false,"P3_secondary_structure":true,"S1_domain_change":false,"S2_biophysics":false,"S3_sae":true},"diff_end":65,"diff_space":"isoform","diff_start":0,"differential_sequence":"MGAEAGRAVGAERSGAARQAGRVAAAAEEAAAAGPRSGGDAGGGGGPGGRGPGPRGGGSGGGGGR","existence_evaluable":6,"existence_score":6,"functional_evaluable":10,"functional_score":4,"isoform_len":248,"kozak_context":"AGCCGGACTACGG","localization":{"canonical":"Cytoplasm","changed":false,"isoform":"Cytoplasm"},"orf_type":"extended","position":58558576,"reasons":{"C1_primate_conservation":"mean_pident=0.96 (threshold 0.8); frac_intact=0.25","C2_mammalian_conservation":"mean_pident=0.85 (threshold 0.5); frac_intact=0.17","C3_phylop_coding_selection":"phylop_unique=4.01 (threshold 2.0); enrichment=0.71 (context)","D1_multi_cell_line":"n_cell_lines=6 (threshold 1)","D2_initiation_efficiency":"max_efficiency=0.119 (threshold 0.01)","D3_mass_spec":"n_validated_unique_peptides=5 (threshold 1)","L1_localization_change":"localization features unchanged (prediction/signals/membrane)","L2_targeting_change":"no targeting change flagged","M1_pathogenic_variant_enrichment":"constraint_enrichment=106.12 (\u22652.0); gnomad_depletion_ratio=1.19 (<0.8)","M2_clinical_variant_overlap":"disease_enrichment_ratio=0.12 (\u22651.0); disease unique=5, shared=113","P1_structured_extension":"plddt_diffregion_mean=0.787 (folded, threshold 0.7)","P2_shared_structural_change":"shared-region C\u03b1 RMSD 1.48 \u00c5 (< 2.0 \u00c5 threshold), TM-score 0.95, 183 aa, min shared pLDDT 0.87","P3_secondary_structure":"17 aa helix at 16-32 (pLDDT 0.75, thresholds 6 aa / 0.7)","S1_domain_change":"n_real_domains_changed_in_diff_region=0","S2_biophysics":"whole-protein |delta| distinct=none (3/3 descriptors evaluable)","S3_sae":"top shared-feature |delta| 11.54 vs threshold 10.0; 158 gained + 36 lost features"},"start_codon":"ACG","strand":"-","structure":{"canonical_cif":"UBE2M__canonical__183aa.cif","isoform_cif":"UBE2M__extended__248aa__chr19-58558576---ACG-ENST00000253023.8.cif","plddt_diffregion_mean":0.7865062291805561,"plddt_isoform_mean":0.8734005915541803,"rmsd_global":1.4440469528361528,"tm_score":0.8269554609321399},"tis_id":"chr19:58558576:-:ACG:ENST00000253023.8","transcript_id":"ENST00000253023.8","variants":{"n_pathogenic_in_unique_region":0,"n_total":424,"pathogenic_in_unique_region":[]}}],"keywords":["catalytic activity, acting on a protein","transferase activity","protein tag activity","Metabolism of proteins","Cell Cycle","DNA Repair","Immune System","Signal Transduction"],"llm":null,"location":"nucleus; cytosol","name":"UBE2M","uniprot_id":"P61081","uniprot_url":"https://www.uniprot.org/uniprotkb/P61081/entry"}}