PPIE

Summary

PPIE (peptidylprolyl isomerase E, HGNC:9258) is a protein-coding gene on chromosome 1p34.2, encoding Peptidyl-prolyl cis-trans isomerase E (Q9UNP9). Involved in pre-mRNA splicing as component of the spliceosome. It is a selective cancer dependency (DepMap: 59.4% of cell lines).

The protein encoded by this gene is a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family. PPIases catalyze the cis-trans isomerization of proline imidic peptide bonds in oligopeptides and accelerate the folding of proteins. This protein contains a highly conserved cyclophilin (CYP) domain as well as an RNA-binding domain. It was shown to possess PPIase and protein folding activities, and it also exhibits RNA-binding activity. Alternative splicing results in multiple transcript variants. A related pseudogene, which is also located on chromosome 1, has been identified.

Source: NCBI Gene 10450 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 48 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 59.4% of screened cell lines
• MANE Select transcript: NM_006112

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9258
Approved symbol	PPIE
Name	peptidylprolyl isomerase E
Location	1p34.2
Locus type	gene with protein product
Status	Approved
Aliases	CyP-33, MGC3736, MGC111222, CypE
Ensembl gene	ENSG00000084072
Ensembl biotype	protein_coding
OMIM	602435
Entrez	10450

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 16 protein_coding, 3 retained_intron, 3 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000324379, ENST00000356511, ENST00000372830, ENST00000372835, ENST00000456578, ENST00000467741, ENST00000470018, ENST00000470213, ENST00000474804, ENST00000475350, ENST00000480169, ENST00000482751, ENST00000485507, ENST00000495526, ENST00000497370, ENST00000871304, ENST00000871305, ENST00000871306, ENST00000871307, ENST00000871308, ENST00000915535, ENST00000915536, ENST00000915537, ENST00000915538

RefSeq mRNA: 4 — MANE Select: NM_006112 NM_001195007, NM_001319293, NM_006112, NM_203456

CCDS: CCDS442, CCDS443, CCDS53299

Canonical transcript exons

ENST00000324379 — 10 exons

Exon	Start	End
ENSE00001829050	39738882	39738931
ENSE00002143267	39753287	39756769
ENSE00003471988	39741895	39741921
ENSE00003497878	39743824	39743924
ENSE00003590352	39743216	39743297
ENSE00003602750	39740165	39740263
ENSE00003671322	39748903	39749088
ENSE00003690009	39745375	39745498
ENSE00003690343	39741366	39741409
ENSE00003791261	39752910	39753052

Expression profiles

Bgee: expression breadth ubiquitous, 283 present calls, max score 94.88.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.9909 / max 257.0062, expressed in 1810 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
2323	25.9315	1810
2322	0.0594	27

Top tissues by expression

294 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	94.88	gold quality
right uterine tube	UBERON:0001302	94.83	gold quality
right testis	UBERON:0004534	94.83	gold quality
body of pancreas	UBERON:0001150	94.76	gold quality
granulocyte	CL:0000094	94.45	gold quality
descending thoracic aorta	UBERON:0002345	94.06	gold quality
islet of Langerhans	UBERON:0000006	94.02	gold quality
muscle layer of sigmoid colon	UBERON:0035805	93.93	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	93.63	gold quality
lower esophagus muscularis layer	UBERON:0035833	93.56	gold quality
lower esophagus	UBERON:0013473	93.55	gold quality
popliteal artery	UBERON:0002250	93.51	gold quality
tibial artery	UBERON:0007610	93.50	gold quality
thoracic aorta	UBERON:0001515	93.49	gold quality
left ovary	UBERON:0002119	93.46	gold quality
ascending aorta	UBERON:0001496	93.45	gold quality
ventricular zone	UBERON:0003053	93.44	gold quality
aorta	UBERON:0000947	93.42	gold quality
right ovary	UBERON:0002118	93.20	gold quality
mucosa of transverse colon	UBERON:0004991	93.17	gold quality
tibial nerve	UBERON:0001323	93.16	gold quality
pancreas	UBERON:0001264	93.15	gold quality
testis	UBERON:0000473	93.11	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	93.11	gold quality
left coronary artery	UBERON:0001626	93.09	gold quality
body of uterus	UBERON:0009853	93.08	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	92.99	gold quality
stromal cell of endometrium	CL:0002255	92.98	gold quality
right coronary artery	UBERON:0001625	92.82	gold quality
left uterine tube	UBERON:0001303	92.73	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

80 targeting PPIE, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-6794-5P	99.76	66.38	1048
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-4716-3P	99.69	66.73	1022
HSA-MIR-7156-5P	99.64	68.81	1369
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-182-3P	99.57	67.57	825
HSA-MIR-4328	99.57	71.06	4094
HSA-MIR-6716-5P	99.56	68.62	1244
HSA-MIR-7159-5P	99.53	72.12	2472
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-4437	99.52	65.29	1266
HSA-MIR-4498	99.47	67.42	2360

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 59.4% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 8)

• The results show that hCyP33 binds specifically to mRNA, namely poly(A)(+)RNA, and that binding stimulates the PPIase activity of hCyP33. (PMID:18258190)
• Data provide insight into the multiple functions of Cyp33 RRM and suggest a Cyp33-dependent mechanism for regulating the transcriptional activity of MLL. (PMID:20460131)
• PPIase domain of CyP33 regulates the conformation of MLL1 through proline isomerization within the PHD3-Bromo linker, thereby disrupting the PHD3-Bromo interface and facilitating binding of the MLL1-PHD3 domain to the CyP33-RRM domain. (PMID:20541251)
• binding of H3K4me3 to PHD3 domain of MLL and binding of the CYP33 RRM domain to PHD3 are mutually inhibitory, implying that PHD3 is a molecular switch for the transition between activation and repression of target genes (PMID:20677832)
• CypE is a host restriction factor that inhibits the functions of nucleoprotein, as well as viral replication and transcription, by impairing the formation of the viral ribonucleoprotein complex. (PMID:21887220)
• Study of datasets analyzing the gene expression profiles and DNA methylation data of gestational Diabetes Mellitus (GDM) and confirmed through real time PCR in placenta tissue of three GDM samples and three normal samples identified Oas1, Ppie, Polr2g as possible pathogenic target genes of GDM by combining protein-protein interaction analysis. (PMID:30389953)
• Cyp33 binds AU-rich RNA motifs via an extended interface that competitively disrupts the gene repressive Cyp33-MLL1 interaction in vitro. (PMID:33606679)
• RNA binding induces an allosteric switch in Cyp33 to repress MLL1-mediated transcription. (PMID:37075125)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ppie	ENSDARG00000103234
mus_musculus	Ppie	ENSMUSG00000028651
rattus_norvegicus	Ppie	ENSRNOG00000014762
drosophila_melanogaster	Cyp40	FBGN0036020
caenorhabditis_elegans		WBGENE00000885

Paralogs (22): PPIL2 (ENSG00000100023), PPIF (ENSG00000108179), PPWD1 (ENSG00000113593), NKTR (ENSG00000114857), PPIL4 (ENSG00000131013), PPIL1 (ENSG00000137168), PPIG (ENSG00000138398), CWC27 (ENSG00000153015), PPIB (ENSG00000166794), PPIC (ENSG00000168938), PPID (ENSG00000171497), PPIH (ENSG00000171960), PPIL6 (ENSG00000185250), PPIA (ENSG00000196262), PPIAL4G (ENSG00000236334), PPIL3 (ENSG00000240344), PPIAL4A (ENSG00000263353), PPIAL4H (ENSG00000270339), PPIAL4E (ENSG00000271567), PPIAL4F (ENSG00000279782), PPIAL4C (ENSG00000288867), PPIAL4D (ENSG00000289549)

Protein

Protein identifiers

Peptidyl-prolyl cis-trans isomerase E — Q9UNP9 (reviewed: Q9UNP9)

Alternative names: Cyclophilin E, Cyclophilin-33, Rotamase E

All UniProt accessions (8): Q9UNP9, E9PEQ6, E9PIB0, E9PK21, E9PKY5, E9PMH0, H0YCV4, H0YE31

UniProt curated annotations — full annotation on UniProt →

Function. Involved in pre-mRNA splicing as component of the spliceosome. Combines RNA-binding and PPIase activities. Binds mRNA and has a preference for single-stranded RNA molecules with poly-A and poly-U stretches, suggesting it binds to the poly(A)-region in the 3’-UTR of mRNA molecules. Catalyzes the cis-trans isomerization of proline imidic peptide bonds in proteins. Inhibits KMT2A activity; this requires proline isomerase activity.

Subunit / interactions. Identified in the spliceosome C complex. Component of the XAB2 complex, a multimeric protein complex composed of XAB2, PRPF19, AQR, ZNF830, ISY1, and PPIE. Identified in a pentameric intron-binding (IB) complex composed of AQR, XAB2, ISY1, ZNF830 and PPIE that is incorporated into the spliceosome as a preassembled complex. The IB complex does not contain PRPF19. Interacts (via RNA-binding domain) with KMT2A (via the third PHD-type zinc-finger).

Subcellular location. Nucleus.

Tissue specificity. Found in all the examined tissues including heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.

Activity regulation. Enzyme activity is inhibited by cyclosporin A.

Domain organisation. The RRM domain mediates both interaction with RNA and with KMT2A (via the third PHD-type zinc-finger), but has much higher affinity for the KMT2A PHD-type zinc-finger.

Similarity. Belongs to the cyclophilin-type PPIase family. PPIase E subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9UNP9-1	A	yes
Q9UNP9-2	B
Q9UNP9-3	3, Cyclophilin-33B

RefSeq proteins (4): NP_001181936, NP_001306222, NP_006103, NP_982281 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000504	RRM_dom	Domain
IPR002130	Cyclophilin-type_PPIase_dom	Domain
IPR012677	Nucleotide-bd_a/b_plait_sf	Homologous_superfamily
IPR016304	PPIE	Family
IPR020892	Cyclophilin-type_PPIase_CS	Conserved_site
IPR029000	Cyclophilin-like_dom_sf	Homologous_superfamily
IPR034168	PPIE_RRM	Domain
IPR035979	RBD_domain_sf	Homologous_superfamily

Pfam: PF00076, PF00160

Enzyme classification (BRENDA):

• EC 5.2.1.8 — peptidylprolyl isomerase (BRENDA: 69 organisms, 374 substrates, 222 inhibitors, 24 Km, 30 kcat entries)

Substrate kinetics (BRENDA)

11 substrates with measured Km, best-characterized 11. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
N-SUCCINYL-ALA-GLU-(TRANS)-PRO-PHE-4-NITROANILID	0.17–0.7	5
N-SUCCINYL-ALA-ALA-(CIS)-PRO-PHE-4-NITROANILIDE	0.104–0.814	2
RNASE T1	0.0004–0.0006	2
SUCCINYL-ALA-ALA-PRO-PHE 4-NITROANILIDE	0.451–1.247	2
SUCCINYL-ALA-LYS-PRO-PHE-4-NITROANILIDE	0.585–0.788	2
ALA-GLY-PSI[CS-N]-PRO-PHE-4-NITROANILIDE	0.53	1
N-SUCCINYL-ALA-LEU-(CIS)-PRO-PHE-4-NITROANILIDE	0.059	1
SUCCINYL-ALA-GLU-PRO-PHE-7-AMIDO-4-METHYLCOUMARI	0.12	1
TRYWNAKMK-(CIS)-PFIFGA	2	1
SUCCINYL-ALA-ALA-(CIS)-PRO-LYS-4-METHYLCOUMARIN-	—	0
SUCCINYL-ALA-ALA-(CIS)-PRO-PHE 4-METHYLCOUMARIN	—	0

Catalyzed reactions (Rhea), 1 shown:

• [protein]-peptidylproline (omega=180) = [protein]-peptidylproline (omega=0) (RHEA:16237)

UniProt features (57 total): strand 16, mutagenesis site 12, turn 9, helix 8, sequence conflict 3, modified residue 3, domain 2, splice variant 2, chain 1, region of interest 1

Structure

Experimental structures (PDB)

36 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
2R99	X-RAY DIFFRACTION	1.61
3MDF	X-RAY DIFFRACTION	1.85
1ZMF	X-RAY DIFFRACTION	1.88
3LPY	X-RAY DIFFRACTION	2
3UCH	X-RAY DIFFRACTION	2.5
8C6J	ELECTRON MICROSCOPY	2.8
6ID1	ELECTRON MICROSCOPY	2.86
6ID0	ELECTRON MICROSCOPY	2.9
6ICZ	ELECTRON MICROSCOPY	3
8I0R	ELECTRON MICROSCOPY	3
8I0T	ELECTRON MICROSCOPY	3
8I0V	ELECTRON MICROSCOPY	3
8I0U	ELECTRON MICROSCOPY	3.3
9FMD	ELECTRON MICROSCOPY	3.3
8I0P	ELECTRON MICROSCOPY	3.4
8I0W	ELECTRON MICROSCOPY	3.4
7W59	ELECTRON MICROSCOPY	3.6
7W5A	ELECTRON MICROSCOPY	3.6
5YZG	ELECTRON MICROSCOPY	4.1
8I0S	ELECTRON MICROSCOPY	4.2
7W5B	ELECTRON MICROSCOPY	4.3
6FF7	ELECTRON MICROSCOPY	4.5
7A5P	ELECTRON MICROSCOPY	5
5Z56	ELECTRON MICROSCOPY	5.1
5MQF	ELECTRON MICROSCOPY	5.9
8CH6	ELECTRON MICROSCOPY	5.9
5Z57	ELECTRON MICROSCOPY	6.5
7ABI	ELECTRON MICROSCOPY	8
2CQB	SOLUTION NMR
2KU7	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UNP9-F1	83.11	0.55

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (3): 91, 97, 119

Mutagenesis-validated functional residues (12):

Position	Phenotype
39	decreased affinity for kmt2a.
40–45	abolishes interaction with kmt2a.
42	slightly decreased affinity for kmt2a.
45	no effect on interaction with kmt2a.
47	no effect on interaction with kmt2a.
49	strongly decreased affinity for kmt2a. decreased affinity for rna.
51	impairs protein folding.
51	abolishes interaction with kmt2a. abolishes inhibition of kmt2a activity.
191	expected to disrupt proline isomerase activity. abolishes inhibition of kmt2a activity; when associated with a-196.
196–197	expected to disrupt peptidylproline binding. decreases interaction with kmt2a. abolishes inhibition of kmt2a activity.
196	expected to disrupt proline isomerase activity. abolishes inhibition of kmt2a activity; when associated with a-191.
9	decreased affinity for rna.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-6781823	Formation of TC-NER Pre-Incision Complex
R-HSA-6781827	Transcription-Coupled Nucleotide Excision Repair (TC-NER)
R-HSA-6782135	Dual incision in TC-NER
R-HSA-6782210	Gap-filling DNA repair synthesis and ligation in TC-NER
R-HSA-6798695	Neutrophil degranulation
R-HSA-72163	mRNA Splicing - Major Pathway
R-HSA-9918481	Dengue Virus-Host Interactions

MSigDB gene sets: 171 (showing top): MORF_DNMT1, REACTOME_INNATE_IMMUNE_SYSTEM, GOCC_SECRETORY_GRANULE, MORF_SNRP70, MORF_HDAC1, GOBP_POSITIVE_REGULATION_OF_VIRAL_GENOME_REPLICATION, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, GOBP_PROTEIN_MATURATION, REACTOME_PROCESSING_OF_CAPPED_INTRON_CONTAINING_PRE_MRNA, TCF11_01, chr1p34, MORF_BUB3, GOBP_RNA_SPLICING, GOBP_VIRAL_GENOME_REPLICATION, MORF_PRKDC

GO Biological Process (7): mRNA splicing, via spliceosome (GO:0000398), regulation of DNA-templated transcription (GO:0006355), protein folding (GO:0006457), positive regulation of viral genome replication (GO:0045070), protein peptidyl-prolyl isomerization (GO:0000413), mRNA processing (GO:0006397), RNA splicing (GO:0008380)

GO Molecular Function (8): RNA binding (GO:0003723), mRNA binding (GO:0003729), peptidyl-prolyl cis-trans isomerase activity (GO:0003755), poly(A) binding (GO:0008143), cyclosporin A binding (GO:0016018), nucleic acid binding (GO:0003676), protein binding (GO:0005515), isomerase activity (GO:0016853)

GO Cellular Component (12): extracellular region (GO:0005576), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), nuclear speck (GO:0016607), secretory granule lumen (GO:0034774), U2-type catalytic step 2 spliceosome (GO:0071007), catalytic step 2 spliceosome (GO:0071013), ficolin-1-rich granule lumen (GO:1904813), spliceosomal complex (GO:0005681), protein-containing complex (GO:0032991)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Transcription-Coupled Nucleotide Excision Repair (TC-NER)	3
Nucleotide Excision Repair	1
Innate Immune System	1
mRNA Splicing	1
Dengue Virus Infection	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
binding	3
RNA processing	2
RNA splicing, via transesterification reactions with bulged adenosine as nucleophile	1
mRNA processing	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
cellular process	1
protein maturation	1
viral genome replication	1
regulation of viral genome replication	1
positive regulation of viral process	1
peptidyl-proline modification	1
mRNA metabolic process	1
nucleic acid binding	1
RNA binding	1
cis-trans isomerase activity	1
catalytic activity, acting on a protein	1
poly-purine tract binding	1
catalytic activity	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
nuclear ribonucleoprotein granule	1
secretory granule	1
cytoplasmic vesicle lumen	1
U2-type spliceosomal complex	1
U2 snRNP	1
U6 snRNP	1
catalytic step 2 spliceosome	1
Prp19 complex	1
spliceosomal complex	1
U5 snRNP	1
catalytic complex	1
intracellular organelle lumen	1
ficolin-1-rich granule	1
nuclear protein-containing complex	1
ribonucleoprotein complex	1

Protein interactions and networks

STRING

2710 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PPIE	ZNF830	Q96NB3	926
PPIE	PRPF19	Q9UMS4	846
PPIE	UNC119	Q13432	839
PPIE	MYCL	P12524	729
PPIE	AQR	O60306	649
PPIE	EGLN3	Q9H6Z9	648
PPIE	SP140	Q13342	638
PPIE	XAB2	Q9HCS7	624
PPIE	CNTD1	Q8N815	620
PPIE	KMT2A	Q03164	615
PPIE	CDC5L	Q99459	570
PPIE	SPO11	Q9Y5K1	556
PPIE	ELOA	Q14241	519
PPIE	XPA	P23025	491
PPIE	POGZ	Q7Z3K3	488

IntAct

148 interactions, top by confidence:

A	B	Type	Score
XAB2	PPIE	psi-mi:“MI:0915”(physical association)	0.910
PPIE	XAB2	psi-mi:“MI:0915”(physical association)	0.910
PPIE	AQR	psi-mi:“MI:0915”(physical association)	0.810
AQR	PPIE	psi-mi:“MI:0407”(direct interaction)	0.810
PPIE	AQR	psi-mi:“MI:0407”(direct interaction)	0.810
PPIE	AQR	psi-mi:“MI:0914”(association)	0.810
PRPF19	PLRG1	psi-mi:“MI:0914”(association)	0.770
SNRPE	GEMIN2	psi-mi:“MI:0914”(association)	0.770
AQR	ZNF830	psi-mi:“MI:0915”(physical association)	0.760
AQR	ZNF830	psi-mi:“MI:0914”(association)	0.760
SLC19A2	ATP5F1B	psi-mi:“MI:0914”(association)	0.730
SYF2	AQR	psi-mi:“MI:0914”(association)	0.730
SNRPG	GEMIN2	psi-mi:“MI:0914”(association)	0.710
PPIE	KMT2A	psi-mi:“MI:0407”(direct interaction)	0.700
KMT2A	PPIE	psi-mi:“MI:0407”(direct interaction)	0.700
KMT2A	PPIE	psi-mi:“MI:0915”(physical association)	0.700
H3C1	KMT2A	psi-mi:“MI:0915”(physical association)	0.680
H3C1	KMT2A	psi-mi:“MI:0407”(direct interaction)	0.680

BioGRID (399): PPIE (Two-hybrid), XAB2 (Two-hybrid), PPIE (Affinity Capture-MS), PPIE (Affinity Capture-MS), PPIE (Affinity Capture-MS), ACBD3 (Affinity Capture-MS), ISY1 (Affinity Capture-MS), XAB2 (Affinity Capture-MS), ZNF830 (Affinity Capture-MS), BUD31 (Affinity Capture-MS), RBM22 (Affinity Capture-MS), AQR (Affinity Capture-MS), TRMT61B (Affinity Capture-MS), CDC5L (Affinity Capture-MS), CCDC12 (Affinity Capture-MS)

ESM2 similar proteins: A4FV72, B3A0R0, D4AY02, O49605, O93826, O94273, P0C1H9, P0C1I0, P0C1I1, P0C1I2, P0C1I3, P0CP78, P0CP79, P23285, P24368, P24369, P26882, P35176, P52009, P52018, P53691, Q08752, Q11004, Q26548, Q2U0E0, Q2UGK2, Q4G338, Q4HXF6, Q4IPH4, Q4WIF3, Q4WP12, Q5ACI8, Q5B4E7, Q5B4R3, Q5R723, Q5U8Z7, Q6BXZ7, Q6C4W6, Q6CBP4, Q6CL78

Diamond homologs: A0A075B759, A0A075B767, A0A0B4J2A2, A0A0R0H9T5, A4FV72, D4AY02, F5H284, H2QII6, O00060, O49886, O93826, P0C1H7, P0C1H8, P0C1I2, P0C1I7, P0C1I8, P0C1I9, P0CP78, P0CP79, P0DN26, P0DN37, P10111, P10255, P14088, P14832, P14851, P17742, P18253, P21568, P21569, P22011, P24367, P24525, P25007, P25719, P29117, P30404, P30405, P34790, P34791

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 114 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Metabolism of non-coding RNA	5	40.1×	4e-06
mRNA Splicing	22	30.6×	3e-25
mRNA Splicing - Major Pathway	36	24.9×	9e-40
Processing of Capped Intron-Containing Pre-mRNA	23	23.9×	5e-24
mRNA Polyadenylation	18	20.0×	3e-17
mRNA Splicing - Minor Pathway	7	19.8×	2e-06
RNA Polymerase II Transcription Termination	7	19.5×	2e-06
CHD1 and CHD2 subfamily	13	17.9×	1e-11

GO biological processes:

GO term	Partners	Fold	FDR
U2-type prespliceosome assembly	10	69.3×	2e-14
spliceosomal snRNP assembly	8	51.6×	2e-10
spliceosomal complex assembly	6	40.1×	7e-07
mRNA splicing, via spliceosome	35	35.6×	3e-43
RNA splicing, via transesterification reactions	5	34.7×	2e-05
RNA splicing	15	14.7×	1e-11
RNA processing	5	12.2×	3e-03
mRNA processing	8	7.0×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

48 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	30
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1914 predictions. Top by Δscore:

Variant	Effect	Δscore
1:39740159:TTGCA:T	acceptor_loss	1.0000
1:39740160:TGCA:T	acceptor_loss	1.0000
1:39740161:GCAGG:G	acceptor_loss	1.0000
1:39740162:CAGG:C	acceptor_loss	1.0000
1:39740163:A:AG	acceptor_gain	1.0000
1:39740163:A:G	acceptor_loss	1.0000
1:39740163:AGGT:A	acceptor_gain	1.0000
1:39740163:AGGTG:A	acceptor_gain	1.0000
1:39740164:G:A	acceptor_loss	1.0000
1:39740164:G:GG	acceptor_gain	1.0000
1:39740164:GGT:G	acceptor_gain	1.0000
1:39740164:GGTG:G	acceptor_gain	1.0000
1:39740164:GGTGG:G	acceptor_gain	1.0000
1:39740259:AACAG:A	donor_gain	1.0000
1:39740260:ACAG:A	donor_gain	1.0000
1:39740261:CAG:C	donor_gain	1.0000
1:39740261:CAGG:C	donor_loss	1.0000
1:39740262:AG:A	donor_gain	1.0000
1:39740262:AGGTG:A	donor_gain	1.0000
1:39740263:GG:G	donor_gain	1.0000
1:39740263:GGT:G	donor_loss	1.0000
1:39740264:GTGA:G	donor_gain	1.0000
1:39740265:T:A	donor_loss	1.0000
1:39741364:A:AG	acceptor_gain	1.0000
1:39741365:G:GG	acceptor_gain	1.0000
1:39743210:TTTCA:T	acceptor_loss	1.0000
1:39743211:TTCA:T	acceptor_loss	1.0000
1:39743212:TCAGA:T	acceptor_loss	1.0000
1:39743213:CA:C	acceptor_loss	1.0000
1:39743214:A:AG	acceptor_gain	1.0000

AlphaMissense

2008 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:39740218:T:C	F29L	1.000
1:39740220:T:A	F29L	1.000
1:39740220:T:G	F29L	1.000
1:39740221:G:A	G30R	1.000
1:39740221:G:C	G30R	1.000
1:39740222:G:A	G30E	1.000
1:39740222:G:T	G30V	1.000
1:39741378:G:A	G48E	1.000
1:39741380:T:C	F49L	1.000
1:39741381:T:C	F49S	1.000
1:39741382:T:A	F49L	1.000
1:39741382:T:G	F49L	1.000
1:39741383:G:C	A50P	1.000
1:39741384:C:A	A50D	1.000
1:39741386:T:C	F51L	1.000
1:39741388:T:A	F51L	1.000
1:39741388:T:G	F51L	1.000
1:39741390:T:A	V52D	1.000
1:39741907:G:C	A63P	1.000
1:39741908:C:A	A63D	1.000
1:39743235:G:A	G74E	1.000
1:39743238:G:C	R75P	1.000
1:39743250:T:A	V79D	1.000
1:39743259:C:A	A82D	1.000
1:39743826:T:A	W96R	1.000
1:39743826:T:C	W96R	1.000
1:39748962:C:G	H190D	1.000
1:39748965:C:A	R191S	1.000
1:39748966:G:C	R191P	1.000
1:39748980:T:C	F196L	1.000

dbSNP variants (sampled 300 via entrez): RS1000293842 (1:39737122 A>C,T), RS1000304217 (1:39737550 A>C,T), RS1000306617 (1:39743582 G>A,C,T), RS1000653032 (1:39754328 G>T), RS1000667020 (1:39736942 A>G), RS1000876989 (1:39760294 G>A,C), RS1000917853 (1:39748783 G>A), RS1001004780 (1:39754043 A>G), RS1001037277 (1:39754382 C>G,T), RS1001290326 (1:39742910 A>G), RS1001371446 (1:39742479 T>A,C), RS1001372712 (1:39736888 C>A,G), RS1001460090 (1:39736920 G>A), RS1001578151 (1:39742420 A>G), RS1001656459 (1:39742709 A>G)

Disease associations

OMIM: gene MIM:602435 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST006585_919	Blood protein levels	4.000000e-25

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066227 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.89	IC50	13	nM	CHEMBL5556944
7.14	Ki	72	nM	CHEMBL5556944

PubChem BioAssay actives

2 with measured affinity, of 2 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(1S,4S,17S,22E)-N-[2-(2-aminoethoxy)ethyl]-1-benzyl-2,5,15,21,24-pentaoxo-4-[(4-phenylphenyl)methyl]-3,6,16,20,25-pentazatricyclo[23.3.1.08,13]nonacosa-8,10,12,22-tetraene-17-carboxamide	2076418: Inhibition of CypE (unknown origin) expressed in Escherichia coli BL21(DE3) by FLIPR based Chymotrypsin coupled prolyl-isomerase assay	ic50	0.0130	uM

CTD chemical–gene interactions

32 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression	4
FR900359	decreases phosphorylation	1
TAK-243	increases sumoylation	1
triphenyl phosphate	affects expression	1
sodium arsenite	affects binding, increases reaction	1
cobaltous chloride	decreases expression	1
yessotoxin	decreases expression	1
deguelin	increases expression	1
2-palmitoylglycerol	increases expression	1
4-chloro-N-((4-(1,1-dimethylethyl)phenyl)methyl)-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
nutlin 3	affects cotreatment, increases secretion	1
abrine	increases expression	1
pyrachlostrobin	increases expression	1
dorsomorphin	decreases expression, affects cotreatment	1
PP242	increases expression	1
Temozolomide	increases expression	1
Air Pollutants	affects expression, increases abundance	1
Antimycin A	increases expression	1
Atrazine	increases expression	1
Benzo(a)pyrene	affects methylation	1
Cisplatin	increases expression	1
Dactinomycin	affects cotreatment, increases secretion	1
Doxorubicin	increases expression	1
Fluorouracil	increases expression	1
Ivermectin	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Ozone	increases abundance, affects expression	1
Ribonucleotides	affects binding	1
Rotenone	increases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5515836	Binding	Inhibition of CypE (unknown origin) expressed in Escherichia coli BL21(DE3) by FLIPR based Chymotrypsin coupled prolyl-isomerase assay	Emerging and Re-emerging Warheads for Targeted Covalent Inhibitors: An Update. — J Med Chem

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.