PCP4

Summary

PCP4 (Purkinje cell protein 4, HGNC:8742) is a protein-coding gene on chromosome 21q22.2, encoding Calmodulin regulator protein PCP4 (P48539). Functions as a modulator of calcium-binding by calmodulin.

Enables calcium ion binding activity and calmodulin binding activity. Involved in positive regulation of CAMKK-AMPK signaling cascade and positive regulation of neuron differentiation. Located in cytosol and nucleus. Part of protein-containing complex. Biomarker of Huntington’s disease and leiomyoma.

Source: NCBI Gene 5121 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 14 total
• MANE Select transcript: NM_006198

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8742
Approved symbol	PCP4
Name	Purkinje cell protein 4
Location	21q22.2
Locus type	gene with protein product
Status	Approved
Aliases	PEP-19
Ensembl gene	ENSG00000183036
Ensembl biotype	protein_coding
OMIM	601629
Entrez	5121

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 2 protein_coding_CDS_not_defined, 1 protein_coding, 1 nonsense_mediated_decay

ENST00000328619, ENST00000462224, ENST00000467565, ENST00000468717

RefSeq mRNA: 1 — MANE Select: NM_006198 NM_006198

CCDS: CCDS33563

Canonical transcript exons

ENST00000328619 — 3 exons

Exon	Start	End
ENSE00001938571	39867438	39867510
ENSE00003509580	39928984	39929392
ENSE00003668461	39898476	39898527

Expression profiles

Bgee: expression breadth ubiquitous, 245 present calls, max score 100.00.

FANTOM5 (CAGE): breadth broad, TPM avg 58.2799 / max 8615.7024, expressed in 454 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
189188	55.8047	442
189189	1.9968	168
209323	0.1675	82
189191	0.1020	45
209321	0.0889	48
209322	0.0827	49
189190	0.0372	14

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lateral nuclear group of thalamus	UBERON:0002736	100.00	gold quality
lateral globus pallidus	UBERON:0002476	99.92	gold quality
middle frontal gyrus	UBERON:0002702	99.90	gold quality
choroid plexus epithelium	UBERON:0003911	99.87	gold quality
putamen	UBERON:0001874	99.86	gold quality
caudate nucleus	UBERON:0001873	99.85	gold quality
seminal vesicle	UBERON:0000998	99.80	gold quality
nucleus accumbens	UBERON:0001882	99.80	gold quality
pigmented layer of retina	UBERON:0001782	99.73	gold quality
medial globus pallidus	UBERON:0002477	99.57	gold quality
globus pallidus	UBERON:0001875	99.54	gold quality
right lobe of thyroid gland	UBERON:0001119	99.35	gold quality
left lobe of thyroid gland	UBERON:0001120	99.24	gold quality
cerebellar vermis	UBERON:0004720	99.07	gold quality
thyroid gland	UBERON:0002046	99.05	gold quality
cauda epididymis	UBERON:0004360	98.96	gold quality
endocervix	UBERON:0000458	98.80	gold quality
right hemisphere of cerebellum	UBERON:0014890	98.48	gold quality
prostate gland	UBERON:0002367	98.30	gold quality
inferior vagus X ganglion	UBERON:0005363	98.30	gold quality
urethra	UBERON:0000057	98.14	gold quality
corpus epididymis	UBERON:0004359	98.12	gold quality
hypothalamus	UBERON:0001898	97.88	gold quality
substantia nigra pars reticulata	UBERON:0001966	97.72	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	97.55	gold quality
lower esophagus muscularis layer	UBERON:0035833	97.53	gold quality
lower esophagus	UBERON:0013473	97.51	gold quality
paraflocculus	UBERON:0005351	97.50	gold quality
dorsal root ganglion	UBERON:0000044	97.48	gold quality
primary visual cortex	UBERON:0002436	97.47	gold quality

Single-cell (SCXA)

Detected in 15 experiment(s), a significant marker in 13.

Experiment	Marker?	Max mean expression
E-MTAB-7316	yes	7591.99
E-GEOD-135922	yes	2004.32
E-HCAD-5	yes	1607.30
E-MTAB-9154	yes	1401.07
E-MTAB-10485	yes	1011.78
E-HCAD-31	yes	839.89
E-GEOD-124472	yes	635.25
E-GEOD-114530	yes	431.97
E-GEOD-83139	yes	189.66
E-GEOD-137537	yes	17.71
E-MTAB-5061	yes	12.99
E-GEOD-81547	yes	8.12
E-GEOD-98556	no	341.99
E-HCAD-30	no	158.54
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HOXA2, RORA

miRNA regulators (miRDB)

44 targeting PCP4, 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-6873-3P	100.00	71.42	2626
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-556-3P	99.74	68.75	1203
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-4677-5P	99.70	70.09	1940
HSA-MIR-494-3P	99.70	71.45	2795
HSA-MIR-586	99.65	70.40	2051
HSA-MIR-578	99.46	68.36	1787
HSA-MIR-3911	99.38	66.95	1087
HSA-MIR-5683	99.36	68.59	2083
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-6505-3P	99.34	67.39	1071
HSA-MIR-2116-5P	99.32	69.34	1273
HSA-MIR-6739-3P	99.22	68.84	1843
HSA-MIR-10399-5P	99.17	69.87	2610
HSA-MIR-6504-3P	99.17	69.31	2891
HSA-MIR-1286	99.09	66.23	1046
HSA-MIR-155-3P	99.03	67.99	924
HSA-MIR-6830-5P	99.01	68.73	1884

Literature-anchored findings (GeneRIF, showing 14)

• PEP-19 has the potential to alter the Ca2+-binding dynamics of free CaM and CaM that is bound to other target proteins (PMID:14551202)
• The PCP4 promoter is activated by Trichostatin A (TSA) treatment according to promoter reporter assays in HEK 293 cells. (PMID:20494980)
• Data show that Pcp4 overexpression induces precocious neuronal differentiation, and is associated with an increase in CaMKIIdelta activation. (PMID:21491429)
• The calmodulin regulator protein, PEP-19, sensitizes ATP-induced Ca2+ release. (PMID:23204517)
• This study demonstrate that Pcp4 overexpression extended these effects later in development by modulating genes in line with the maturation of neurons in the cerebellum. (PMID:24291518)
• PCP4 is a regulator of aldosterone production in normal, hyperplastic, and neoplastic human adrenocortical cells. (PMID:24403568)
• PCP4 protein is highly expressed in the olfactory bulb and caudate putamen and PCP4 expressing cells in the brain are of neuronal origin. (PMID:24954028)
• Data indicated that PCP4/PEP19 regulates apoptosis but exact mechanism is still unknown. (PMID:25153723)
• PCP4/PEP19 has a role in promoting migration, invasion and adhesion in human breast cancer cells (PMID:27384474)
• PCP4 promoter was one of the most hypomethylated in aldosterone-producing adenoma and PCP4 transcription may be associated with demethylation as well as with CEBPA in APAs. (PMID:29294065)
• Compared to other CaM regulatory proteins, PCP4/PEP-19 transcripts were more abundant in human myometrium. The expression of PCP4/PEP-19 was lowest in myometrium of women with preterm pregnancy and chorioamnionitis. (PMID:30744532)
• PCP4/PEP19 downregulates neurite outgrowth via transcriptional regulation of Ascl1 and NeuroD1 expression in human neuroblastoma M17 cells. (PMID:32641824)
• Circ_0019693 promotes osteogenic differentiation of bone marrow mesenchymal stem cell and enhances osteogenesis-coupled angiogenesis via regulating microRNA-942-5p-targeted purkinje cell protein 4 in the development of osteoporosis. (PMID:35030971)
• PCP4 Promotes Alzheimer’s Disease Pathogenesis by Affecting Amyloid-beta Protein Precursor Processing. (PMID:37302034)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	pcp4a	ENSDARG00000053130
danio_rerio	PCP4	ENSDARG00000110729
mus_musculus	Pcp4	ENSMUSG00000090223
rattus_norvegicus	Pcp4	ENSRNOG00000001628

Paralogs (1): PCP4L1 (ENSG00000248485)

Protein

Protein identifiers

Calmodulin regulator protein PCP4 — P48539 (reviewed: P48539)

Alternative names: Brain-specific polypeptide PEP-19, Purkinje cell protein 4

All UniProt accessions (2): P48539, F6SSA2

UniProt curated annotations — full annotation on UniProt →

Function. Functions as a modulator of calcium-binding by calmodulin. Thereby, regulates calmodulin activity and the different processes it controls. For instance, may play a role in neuronal differentiation through activation of calmodulin-dependent kinase signaling pathways.

Subunit / interactions. Binds to both calcium-free and calcium-bound calmodulin. The affinity for the calcium-bound form is 50-fold greater.

Domain organisation. Mostly intrinsically disordered, with residual structure localized to the IQ domain which mediates the interaction with calmodulin.

Similarity. Belongs to the PCP4 family.

RefSeq proteins (1): NP_006189* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR052142	Calmodulin_Regulator_PCP4-like	Family

UniProt features (14 total): mutagenesis site 6, region of interest 2, chain 1, domain 1, sequence conflict 1, strand 1, helix 1, compositionally biased region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2N77	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P48539-F1	77.56	0.44

Functional residue map

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

Mutagenesis-validated functional residues (6):

Position	Phenotype
40	decreased calmodulin modulator function.
29	no effect on the calmodulin modulator function.
31	decreased calmodulin modulator function.
33	decreased calmodulin modulator function.
35	no effect on the calmodulin modulator function.
37	loss of the calmodulin modulator function.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 172 (showing top): GOBP_REGULATION_OF_CALCIUM_MEDIATED_SIGNALING, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_POSITIVE_REGULATION_OF_NEURON_DIFFERENTIATION, GOZGIT_ESR1_TARGETS_DN, AREB6_01, GOBP_NEUROGENESIS, TOMLINS_PROSTATE_CANCER_DN, MODULE_66, GOBP_POSITIVE_REGULATION_OF_CALCIUM_MEDIATED_SIGNALING, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1, GOBP_REGULATION_OF_NEURON_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_CELL_DIFFERENTIATION, AIYAR_COBRA1_TARGETS_DN, MODULE_165, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION

GO Biological Process (2): positive regulation of neuron differentiation (GO:0045666), positive regulation of CAMKK-AMPK signaling cascade (GO:1905291)

GO Molecular Function (3): calcium ion binding (GO:0005509), calmodulin binding (GO:0005516), protein binding (GO:0005515)

GO Cellular Component (4): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), protein-containing complex (GO:0032991)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
neuron differentiation	1
positive regulation of cell differentiation	1
regulation of neuron differentiation	1
positive regulation of calcium-mediated signaling	1
CAMKK-AMPK signaling cascade	1
regulation of CAMKK-AMPK signaling cascade	1
metal ion binding	1
protein binding	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cytoplasm	1
cellular_component	1

Protein interactions and networks

STRING

1248 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PCP4	CALML6	Q8TD86	980
PCP4	CALML4	Q96GE6	980
PCP4	CALML5	Q9NZT1	980
PCP4	CALML3	P27482	979
PCP4	CALM1	P02593	973
PCP4	ETS2	P15036	697
PCP4	ABCG1	P45844	685
PCP4	RGS14	O43566	633
PCP4	CALB1	P05937	533
PCP4	ARPP21	Q9UBL0	520
PCP4	PVALB	P20472	511
PCP4	HOMER3	Q9NSC5	501
PCP4	AMIGO2	Q86SJ2	494
PCP4	GARNL3	Q5VVW2	489
PCP4	KCNJ6	P48051	484

IntAct

27 interactions, top by confidence:

A	B	Type	Score
SNRPB	SART1	psi-mi:“MI:0914”(association)	0.640
PCP4	CALML6	psi-mi:“MI:0915”(physical association)	0.560
SH3BGRL3	PCP4	psi-mi:“MI:0914”(association)	0.530
TERF2IP	PCP4	psi-mi:“MI:0915”(physical association)	0.510
PCP4	DAPK1	psi-mi:“MI:0407”(direct interaction)	0.440
PCP4	RAB27A	psi-mi:“MI:0915”(physical association)	0.400
PCP4	TERF1	psi-mi:“MI:0915”(physical association)	0.370
PCP4	POT1	psi-mi:“MI:0915”(physical association)	0.370
IQCB1	PCP4L1	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
UBL3	RCCD1	psi-mi:“MI:0914”(association)	0.350
BCAS2	INPPL1	psi-mi:“MI:0914”(association)	0.350
TUSC2	NMT2	psi-mi:“MI:0914”(association)	0.350
SVOPL	RTN2	psi-mi:“MI:0914”(association)	0.350
TMEM196	ZMPSTE24	psi-mi:“MI:0914”(association)	0.350
PCP4	A2ML1	psi-mi:“MI:0914”(association)	0.350
GOLGA7	PCP4	psi-mi:“MI:0914”(association)	0.350
NUDT3	SNRPB	psi-mi:“MI:0914”(association)	0.350
PCP4	RAB39B	psi-mi:“MI:0914”(association)	0.350
SNRPB2	NUDT3	psi-mi:“MI:0914”(association)	0.350
PCP4	TERF2IP	psi-mi:“MI:0915”(physical association)	0.000
PCP4	CALML6	psi-mi:“MI:0915”(physical association)	0.000
PCP4	PAX6	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (46): PCP4 (Reconstituted Complex), PCP4 (Two-hybrid), PCP4 (Affinity Capture-MS), PCP4 (Affinity Capture-MS), PCP4 (Affinity Capture-MS), PCP4 (Affinity Capture-MS), PCP4 (Affinity Capture-MS), PCP4 (Affinity Capture-MS), RAB27A (Affinity Capture-MS), ATP12A (Affinity Capture-MS), PLBD1 (Affinity Capture-MS), TGM1 (Affinity Capture-MS), ACPP (Affinity Capture-MS), CTSD (Affinity Capture-MS), SERPINA3 (Affinity Capture-MS)

ESM2 similar proteins: A0A1B0GV96, A0MZ66, A0MZ67, A2VDA9, A5PJI6, A6NKN8, A8R4Q8, E7F7X0, O14990, O19021, O42932, O62770, O62771, P13505, P36425, P48539, P54866, P63054, P63055, P84086, P84087, P84088, Q04504, Q0P561, Q148C4, Q15506, Q28IH8, Q3UYG8, Q4R615, Q5F3A1, Q5M8L3, Q5R4Q3, Q5ZM33, Q62252, Q62736, Q6DBA5, Q6GNQ4, Q6NWC9, Q6P3G4, Q6PUV4

Diamond homologs: A6NKN8, A8R4Q8, P48539, P63054, P63055, Q148C4, Q6W8Q3

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
RORA	“up-regulates quantity by expression”	PCP4	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	8
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

792 predictions. Top by Δscore:

Variant	Effect	Δscore
21:39888182:T:G	donor_gain	1.0000
21:39928979:TACA:T	acceptor_loss	1.0000
21:39928980:ACAG:A	acceptor_loss	1.0000
21:39928981:CA:C	acceptor_loss	1.0000
21:39928982:A:AG	acceptor_gain	1.0000
21:39928982:AGAT:A	acceptor_gain	1.0000
21:39928982:AGATG:A	acceptor_gain	1.0000
21:39928983:G:GC	acceptor_gain	1.0000
21:39928983:GA:G	acceptor_gain	1.0000
21:39928983:GAT:G	acceptor_gain	1.0000
21:39928983:GATG:G	acceptor_gain	1.0000
21:39928983:GATGG:G	acceptor_gain	1.0000
21:39898467:T:A	acceptor_gain	0.9900
21:39898474:A:AG	acceptor_gain	0.9900
21:39898475:G:GG	acceptor_gain	0.9900
21:39898475:GC:G	acceptor_gain	0.9900
21:39928976:T:A	acceptor_gain	0.9900
21:39928980:A:AG	acceptor_gain	0.9900
21:39928981:C:G	acceptor_gain	0.9900
21:39867506:GTGAG:G	donor_gain	0.9800
21:39888178:GCTGT:G	donor_gain	0.9800
21:39898471:TTTA:T	acceptor_loss	0.9800
21:39898472:TTAGC:T	acceptor_loss	0.9800
21:39898473:TA:T	acceptor_loss	0.9800
21:39898475:G:GT	acceptor_loss	0.9800
21:39898525:ATGGT:A	donor_loss	0.9800
21:39898527:GGTA:G	donor_loss	0.9800
21:39898528:G:A	donor_loss	0.9800
21:39898529:T:G	donor_loss	0.9800
21:39898530:A:AG	donor_loss	0.9800

AlphaMissense

410 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
21:39929059:T:A	I46N	1.000
21:39929059:T:C	I46T	1.000
21:39929055:G:C	A45P	0.999
21:39929059:T:G	I46S	0.999
21:39929063:G:C	Q47H	0.999
21:39929063:G:T	Q47H	0.999
21:39929064:T:C	S48P	0.999
21:39929070:T:C	F50L	0.999
21:39929072:C:A	F50L	0.999
21:39929072:C:G	F50L	0.999
21:39929074:G:C	R51T	0.999
21:39929075:A:C	R51S	0.999
21:39929075:A:T	R51S	0.999
21:39929049:G:C	A43P	0.998
21:39929050:C:A	A43E	0.998
21:39929071:T:C	F50S	0.998
21:39929071:T:G	F50C	0.998
21:39929017:T:A	I32N	0.997
21:39929017:T:G	I32S	0.997
21:39929046:G:C	A42P	0.997
21:39929079:T:C	F53L	0.997
21:39929081:C:A	F53L	0.997
21:39929081:C:G	F53L	0.997
21:39929073:A:G	R51G	0.995
21:39929074:G:T	R51I	0.994
21:39929062:A:C	Q47P	0.993
21:39929083:A:C	Q54P	0.993
21:39929017:T:C	I32T	0.992
21:39929047:C:A	A42E	0.992
21:39929049:G:A	A43T	0.992

dbSNP variants (sampled 300 via entrez): RS1000087964 (21:39904774 A>G), RS1000105368 (21:39881128 G>A,T), RS1000122030 (21:39916487 T>C), RS1000134466 (21:39891749 G>A,T), RS1000205757 (21:39906350 A>G), RS1000218430 (21:39928014 T>A,C), RS1000321655 (21:39885279 A>G), RS1000333307 (21:39876231 T>C), RS1000361051 (21:39897343 C>A,G,T), RS1000476406 (21:39905982 A>G), RS1000486606 (21:39890459 G>A), RS1000495087 (21:39927122 G>A,T), RS1000526857 (21:39866308 T>A,C), RS1000593874 (21:39886287 G>A), RS1000645116 (21:39902738 T>G)

Disease associations

OMIM: gene MIM:601629 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST002307_8	Systolic blood pressure (alcohol consumption interaction)	8.000000e-07
GCST004270_2	Venlafaxine response in generalised anxiety disorder (responders vs non-responders after 12 weeks)	4.000000e-06
GCST009391_1471	Metabolite levels	2.000000e-06
GCST009391_838	Metabolite levels	9.000000e-06
GCST010043_8	Asthma	4.000000e-08

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004329	alcohol drinking
EFO:0006335	systolic blood pressure
EFO:0010407	triacylglycerol 48:4 measurement
EFO:0010399	triacylglycerol 44:1 measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	5
Estradiol	affects cotreatment, decreases expression, increases expression	4
bisphenol A	affects cotreatment, increases methylation, increases expression	2
Nickel	decreases expression	2
beta-lapachone	decreases expression	1
sodium arsenite	affects methylation	1
JP8 aviation fuel	affects expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Coumestrol	increases expression, affects cotreatment	1
Polychlorinated Biphenyls	increases expression	1
Potassium Dichromate	increases expression	1
Rotenone	increases expression	1
Selenium	decreases expression	1
Smoke	increases expression	1
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression	1
Thimerosal	increases expression	1
Triclosan	increases expression	1
Zinc	decreases expression	1
Aflatoxin B1	increases methylation	1
Genistein	increases expression	1

Clinical trials (associated diseases)

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