PCSK1

Summary

PCSK1 (proprotein convertase subtilisin/kexin type 1, HGNC:8743) is a protein-coding gene on chromosome 5q15, encoding Neuroendocrine convertase 1 (P29120). Involved in the processing of hormone and other protein precursors at sites comprised of pairs of basic amino acid residues.

This gene encodes a member of the subtilisin-like proprotein convertase family, which includes proteases that process protein and peptide precursors trafficking through regulated or constitutive branches of the secretory pathway. The encoded protein undergoes an initial autocatalytic processing event in the ER to generate a heterodimer which exits the ER and sorts to subcellular compartments where a second autocatalytic even takes place and the catalytic activity is acquired. The protease is packaged into and activated in dense core secretory granules and expressed in the neuroendocrine system and brain. This gene encodes one of the seven basic amino acid-specific members which cleave their substrates at single or paired basic residues. It functions in the proteolytic activation of polypeptide hormones and neuropeptides precursors. Mutations in this gene have been associated with susceptibility to obesity and proprotein convertase 1/3 deficiency. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene

Source: NCBI Gene 5122 — RefSeq curated summary.

At a glance

• Gene–disease (curated): obesity due to prohormone convertase I deficiency (Definitive, GenCC)
• GWAS associations: 20
• Clinical variants (ClinVar): 41 total — 3 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 29
• Druggable target: yes
• MANE Select transcript: NM_000439

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8743
Approved symbol	PCSK1
Name	proprotein convertase subtilisin/kexin type 1
Location	5q15
Locus type	gene with protein product
Status	Approved
Aliases	PC1, PC3, SPC3, PC1/3
Ensembl gene	ENSG00000175426
Ensembl biotype	protein_coding
OMIM	162150
Entrez	5122

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 6 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000311106, ENST00000508626, ENST00000509190, ENST00000513085, ENST00000868415, ENST00000914384, ENST00000947120

RefSeq mRNA: 2 — MANE Select: NM_000439 NM_000439, NM_001177875

CCDS: CCDS4081, CCDS54881

Canonical transcript exons

ENST00000311106 — 14 exons

Exon	Start	End
ENSE00001206389	96410774	96410986
ENSE00001206401	96416033	96416121
ENSE00001206406	96421880	96421956
ENSE00001206409	96423313	96423459
ENSE00001206416	96425820	96425930
ENSE00001206420	96429213	96429317
ENSE00001206425	96390333	96393378
ENSE00001206427	96432863	96433248
ENSE00003461863	96394864	96395025
ENSE00003493906	96397336	96397469
ENSE00003571272	96412318	96412490
ENSE00003581842	96408223	96408323
ENSE00003636749	96398879	96399036
ENSE00003689995	96399953	96400186

Expression profiles

Bgee: expression breadth ubiquitous, 197 present calls, max score 99.17.

FANTOM5 (CAGE): breadth broad, TPM avg 2.5056 / max 297.7888, expressed in 341 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
62686	2.0473	310
62685	0.1803	80
62683	0.1538	55
62684	0.1242	66

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
type B pancreatic cell	CL:0000169	99.17	gold quality
islet of Langerhans	UBERON:0000006	98.95	gold quality
postcentral gyrus	UBERON:0002581	90.45	gold quality
superior frontal gyrus	UBERON:0002661	89.54	gold quality
orbitofrontal cortex	UBERON:0004167	88.97	gold quality
parietal lobe	UBERON:0001872	88.70	gold quality
Brodmann (1909) area 23	UBERON:0013554	88.62	gold quality
Brodmann (1909) area 46	UBERON:0006483	88.50	gold quality
endothelial cell	CL:0000115	87.32	gold quality
Brodmann (1909) area 10	UBERON:0013541	87.28	gold quality
prefrontal cortex	UBERON:0000451	86.88	gold quality
primary visual cortex	UBERON:0002436	86.55	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.31	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	85.83	gold quality
occipital lobe	UBERON:0002021	85.02	gold quality
frontal cortex	UBERON:0001870	84.86	gold quality
Brodmann (1909) area 9	UBERON:0013540	84.58	gold quality
hypothalamus	UBERON:0001898	84.33	gold quality
frontal pole	UBERON:0002795	83.69	gold quality
neocortex	UBERON:0001950	83.23	gold quality
middle temporal gyrus	UBERON:0002771	82.64	gold quality
pituitary gland	UBERON:0000007	81.08	gold quality
cerebral cortex	UBERON:0000956	80.66	gold quality
cingulate cortex	UBERON:0003027	79.79	gold quality
adenohypophysis	UBERON:0002196	79.65	gold quality
anterior cingulate cortex	UBERON:0009835	79.64	gold quality
right frontal lobe	UBERON:0002810	78.54	gold quality
pancreas	UBERON:0001264	78.49	gold quality
lateral nuclear group of thalamus	UBERON:0002736	77.42	gold quality
entorhinal cortex	UBERON:0002728	76.03	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 9.

Experiment	Marker?	Max mean expression
E-GEOD-81547	yes	2685.41
E-GEOD-83139	yes	1311.13
E-MTAB-9154	yes	1220.46
E-ENAD-27	yes	1061.54
E-HCAD-31	yes	944.34
E-GEOD-81608	yes	930.01
E-MTAB-5061	yes	642.72
E-GEOD-125970	yes	7.43
E-ANND-3	yes	6.18

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, ATF1, CREB1, ID1, ID3, JUN, MAFA, MYC, NKX6-1, PAX1, PAX6, PDX1, REST, STAT6, TCF3, TP53

miRNA regulators (miRDB)

148 targeting PCSK1, 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-4262	100.00	73.26	3931
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502

Literature-anchored findings (GeneRIF, showing 40)

• prominently expressed in PTHrP-expressing human cancer cell lines originating from tumors of the breast, lung, prostate, as well as lymphoma (PMID:11720250)
• Polymorphism associated with insulin resistance affects insulin snssitivity by interacting with PPARgamma2. (PMID:14574455)
• PC1 is present in the human cortex to fulfill its role in proteolytic processing of neuropeptide precursors; no significant change in PC1 levels is observed in Alzheimer patients. (PMID:14614908)
• Data suggest that proprotein convertase 1, presumably in the enteroendocrine cells, is essential for the normal absorptive function of the human small intestine. (PMID:14617756)
• results have implications for the mechanism of granule sorting of PC3 as well as for the topology of PC2 and carboxypeptidase E, which have been reported to span the lipid membrane by homologous charged sequences (PMID:15807527)
• PC1 and PC2 in are abnormally expressed and processed in human colorectal liver metastases (PMID:16293189)
• PC1 has a role in obesity, hyperphagia and increased metabolic efficiency (PMID:16644867)
• A novel missense mutation Ser307Leu in PC 1/3 linked to hyperphagia and obesity. (PMID:17595246)
• defective PC1/3 expression may lead to preferential production of unprocessed, biologically inactive ACTH variants in sient corticotroph adenoma. (PMID:17917309)
• PC1/3 governs the endocrine and PC2 the neuronal processing of proCCK, whereas PC5/6 contributes only to a modest endocrine synthesis of CCK-22. (PMID:18096669)
• Suppression of Pdcd4 resulted in an increased release of CgA and Sg II and was accompanied by an up-regulation of intracellular PC1. (PMID:18549351)
• The nonsynonymous variants of PCSK1 rs6232, encoding N221D, and rs6234-rs6235, encoding the Q665E-S690T pair, were consistently associated with obesity in adults and children (PMID:18604207)
• Function for PAX6 in the regulation of proinsulin processing and glucose metabolism via modulation of PC1/3 production. (PMID:19034419)
• PC1 and PC2 were primarily expressed in neurons, whereas PACE4 appeared to be largely restricted to glia. Thus, elevated PACE4 may modulate the bioactivity of proteins secreted in the ONH and retina. (PMID:19339735)
• PCSK1 rs6232 and rs6235 SNPs are not major contributors to common obesity in the general population; however, the effect of rs6232 may be age-dependent. (PMID:19528091)
• The presence of PC and GOAT in the cells, as well as n-octanoic acid in the culture medium, was necessary to produce n-octanoyl ghrelin. (PMID:19628676)
• Four genes, PCSK1, (P=0.008), EGFR,(P=0.003), PAX4,(P=0.008), and LYN,(P=0.002) consistently yielded statistical evidence for association with longevity. (PMID:19641380)
• common PCSK1 genetic variants are associated with obesity in the Chinese population (PMID:19875984)
• Studies of protease SPC3 (PC1/3) suggest that C-domain sequences contribute to cleavage site selection for proinsulin (PMID:20106974)
• The rs6234 G-allele showed a significant association with increased risk of combined phenotype of obesity and overweight in Chinese. (PMID:20498726)
• Our data suggest that SNPs in or near the PCSK1 locus contribute to obesity risk in the Greek population. (PMID:21720444)
• PCSK1 rs6232 G-allele and rs6235 C-allele have an effect on body composition which may be modified by sex (PMID:21935364)
• triple-variant prohormone convertase 1 underwent significantly more proteolytic processing at the N- and C-termini than the double-variant isoforms (PMID:22000902)
• an increased risk of obesity in heterozygous carriers of mutations in the PCSK1 gene. (PMID:22210313)
• The potential variations in the exons and exon/intron junctions of caprine PC1 gene, were studied. (PMID:22552345)
• PCSK1 SNP rs6235 was associated with essential hypertension and blood pressure in the Han Chinese population (PMID:22592666)
• PCSK1 rs6232 is associated with childhood and adult class III obesity in the Mexican population (PMID:22737226)
• Data show the synthetic effect of SNPs on the indices of adiposity and risk of obesity in Chinese girls, but failed to replicate the effect of five separate variants of SEC16B rs10913469, SH2B1 rs4788102, PCSK1 rs6235, KCTD15 rs29941 and BAT2 rs2844479. (PMID:23121087)
• PC1/3 overexpression induces morphological and phenotypic epithelial-mesenchymal transition changes of airway epithelial cells involved in the pathogenesis of nasal polyps (PMID:23314902)
• novel R80Q (rs1799904) variant both exhibits adverse effects on PC1/3 activity and is prevalent in the population (PMID:23383060)
• Common PCSK1 variants (notably rs6232 and rs6235) contribute modestly to obesity in multi-ethnic American population. (PMID:23451278)
• the development of central diabetes insipidus in this proband suggests that PCSK1 deficiency can be associated with impaired osmoregulation. (PMID:23800642)
• study indicates that the PCSK1 rs6235 SNP may contribute to the risk of overweight in men and predict obesity-related metabolic traits such as waist circumference and diastolic blood pressure in Taiwanese subjects (PMID:24140494)
• The data of this study suggest that defects in the processing of hypothalamic neuropeptides in huntington disease may partially arise from decreased PC1/3 and PC2 expressions. (PMID:24226266)
• PCSK1 is overexpressed in fibrolamellar hepatocellular carcinoma. (PMID:24443104)
• Common genetic variants in PCSK1 are associated with coronary artery disease in Chinese patients with type 2 diabetes. (PMID:24489861)
• Epistases between single nucleotide polymorphisms within proprotein convertase subtilisin/kexin type 1(PCSK1) and dopamine beta-hydroxylase(DBH) genes are significantly associated with susceptibility or resistance to premature ovarian failure (PMID:24618767)
• We showed for the first time that a nonsense mutation in PCSK1 was likely to cause dominantly inherited human obesity, due to the inhibiting properties of the propeptide fragment encoded by the null allele (PMID:24890885)
• PC1/3(S357G) exhibited a lower calcium dependence; a higher pH optimum. (PMID:24932808)
• Thais carrying SNPs rs6234-5 are at increased risk of obesity, and the risk of severe obesity increases when carrying both rs6234-5 and rs3811951, but not with rs271939. Patients with genetic variations at rs3811951 are at risk of having low HDL-C levels. (PMID:24964673)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	pcsk1	ENSDARG00000002600
mus_musculus	Pcsk1	ENSMUSG00000021587
rattus_norvegicus	Pcsk1	ENSRNOG00000011107

Paralogs (9): PCSK5 (ENSG00000099139), PCSK4 (ENSG00000115257), PCSK2 (ENSG00000125851), TPP2 (ENSG00000134900), PCSK6 (ENSG00000140479), FURIN (ENSG00000140564), MBTPS1 (ENSG00000140943), PCSK7 (ENSG00000160613), PCSK9 (ENSG00000169174)

Protein

Protein identifiers

Neuroendocrine convertase 1 — P29120 (reviewed: P29120)

Alternative names: Prohormone convertase 1, Proprotein convertase 1

All UniProt accessions (2): D6RJA3, P29120

UniProt curated annotations — full annotation on UniProt →

Function. Involved in the processing of hormone and other protein precursors at sites comprised of pairs of basic amino acid residues. Substrates include POMC, renin, enkephalin, dynorphin, somatostatin, insulin and AGRP.

Subcellular location. Cytoplasmic vesicle. Secretory vesicle.

Post-translational modifications. O-glycosylated.

Disease relevance. Proprotein convertase 1 deficiency (PC1 deficiency) [MIM:600955] Characterized by obesity, hypogonadism, hypoadrenalism, reactive hypoglycemia as well as marked small-intestinal absorptive dysfunction It is due to impaired processing of prohormones. The disease is caused by variants affecting the gene represented in this entry.

Polymorphism. Genetic variations in PCSK1 define the body mass index quantitative trait locus 12 (BMIQ12) [MIM:612362]. Variance in body mass index is a susceptibility factor for obesity.

Similarity. Belongs to the peptidase S8 family. Furin subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
P29120-1	1	yes
P29120-2	2

RefSeq proteins (2): NP_000430, NP_001171346 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000209	Peptidase_S8/S53_dom	Domain
IPR002884	P_dom	Domain
IPR008979	Galactose-bd-like_sf	Homologous_superfamily
IPR015500	Peptidase_S8_subtilisin-rel	Family
IPR022005	Proho_convert	Domain
IPR022398	Peptidase_S8_His-AS	Active_site
IPR023827	Peptidase_S8_Asp-AS	Active_site
IPR023828	Peptidase_S8_Ser-AS	Active_site
IPR032815	S8_pro-domain	Domain
IPR034182	Kexin/furin	Domain
IPR036852	Peptidase_S8/S53_dom_sf	Homologous_superfamily
IPR038466	S8_pro-domain_sf	Homologous_superfamily

Pfam: PF00082, PF01483, PF12177, PF16470

Enzyme classification (BRENDA):

• EC 3.4.21.93 — Proprotein convertase 1 (BRENDA: 8 organisms, 63 substrates, 46 inhibitors, 2 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

2 substrates with measured Km, best-characterized 2. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
(2-AMINOBENZOYL)-LYS-GLU-ARG-SER-LYS-ARG-SER-ALA	0.017	1
PGLU-ARG-THR-LYS-ARG 4-METHYLCOUMARIN 1-AMIDE	0.023	1

UniProt features (28 total): sequence variant 7, active site 3, glycosylation site 3, disulfide bond 3, sequence conflict 3, domain 2, compositionally biased region 2, signal peptide 1, propeptide 1, splice variant 1, chain 1, region of interest 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
9FIC	X-RAY DIFFRACTION	1.3
9FIE	X-RAY DIFFRACTION	2
9FID	X-RAY DIFFRACTION	2.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P29120-F1	82.40	0.66

Functional residue map

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

Catalytic / active sites (3): 382 (charge relay system); 167 (charge relay system); 208 (charge relay system)

Disulfide bonds (3): 225–374, 317–347, 467–494

Glycosylation sites (3): 173, 401, 632

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-209952	Peptide hormone biosynthesis
R-HSA-264876	Insulin processing
R-HSA-381771	Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1)
R-HSA-400511	Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP)
R-HSA-422085	Synthesis, secretion, and deacylation of Ghrelin
R-HSA-2980736	Peptide hormone metabolism
R-HSA-392499	Metabolism of proteins
R-HSA-400508	Incretin synthesis, secretion, and inactivation

MSigDB gene sets: 267 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_UP, E2F_Q4, MODULE_92, FREAC2_01, E2F4DP1_01, GOCC_SECRETORY_GRANULE, GOBP_REGULATION_OF_HORMONE_LEVELS, CREBP1_Q2, GOBP_CELL_CELL_SIGNALING, CREB_Q4, GOBP_PEPTIDE_METABOLIC_PROCESS, MODULE_66, E2F1DP1_01, GOBP_PROTEIN_MATURATION

GO Biological Process (6): proteolysis (GO:0006508), cell-cell signaling (GO:0007267), peptide hormone processing (GO:0016486), insulin processing (GO:0030070), peptide biosynthetic process (GO:0043043), protein processing (GO:0016485)

GO Molecular Function (6): serine-type endopeptidase activity (GO:0004252), identical protein binding (GO:0042802), endopeptidase activity (GO:0004175), peptidase activity (GO:0008233), serine-type peptidase activity (GO:0008236), hydrolase activity (GO:0016787)

GO Cellular Component (7): obsolete extracellular space (GO:0005615), membrane (GO:0016020), transport vesicle (GO:0030133), secretory granule lumen (GO:0034774), neuron projection (GO:0043005), secretory granule (GO:0030141), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Peptide hormone metabolism	4
Incretin synthesis, secretion, and inactivation	2
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
peptidase activity	2
endomembrane system	2
protein metabolic process	1
cell communication	1
signaling	1
hormone metabolic process	1
signaling receptor ligand precursor processing	1
peptide hormone processing	1
insulin metabolic process	1
peptide metabolic process	1
biosynthetic process	1
proteolysis	1
protein maturation	1
endopeptidase activity	1
serine-type peptidase activity	1
protein binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
serine hydrolase activity	1
catalytic activity	1
cellular anatomical structure	1
cytoplasmic vesicle	1
secretory granule	1
cytoplasmic vesicle lumen	1
plasma membrane bounded cell projection	1
secretory vesicle	1
cytoplasm	1
intracellular vesicle	1

Protein interactions and networks

STRING

2620 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PCSK1	RIPK3	Q9Y572	884
PCSK1	CPE	P16870	882
PCSK1	RIPK1	Q13546	877
PCSK1	MC4R	P32245	851
PCSK1	MLKL	Q8NB16	850
PCSK1	PCSK1N	Q9UHG2	833
PCSK1	LEP	P41159	804
PCSK1	FTO	Q9C0B1	801
PCSK1	POMC	P01189	796
PCSK1	MC3R	P41968	748
PCSK1	SH2B1	Q9NRF2	746
PCSK1	SCG5	P01164	720
PCSK1	LEPR	P48357	684
PCSK1	CASP8	Q14790	680
PCSK1	GNPDA2	Q8TDQ7	673

IntAct

7 interactions, top by confidence:

A	B	Type	Score
S	PCSK1	psi-mi:“MI:0570”(protein cleavage)	0.440
PCSK1	H1-2	psi-mi:“MI:0915”(physical association)	0.400
SDHA	HMGB3	psi-mi:“MI:0914”(association)	0.350
SDHA	NME2P1	psi-mi:“MI:0914”(association)	0.350
DYRK1A	TEX13D	psi-mi:“MI:0914”(association)	0.350
PCSK1	HS6ST1	psi-mi:“MI:0914”(association)	0.350

BioGRID (14): PCSK1 (Affinity Capture-MS), PCSK1 (Proximity Label-MS), PCSK1 (Affinity Capture-MS), DCAF6 (Affinity Capture-MS), ITIH2 (Affinity Capture-MS), BDH2 (Affinity Capture-MS), ABCB6 (Affinity Capture-MS), ACADSB (Affinity Capture-MS), B4GALT6 (Affinity Capture-MS), HS6ST1 (Affinity Capture-MS), PCSK1 (Affinity Capture-MS), PCSK1 (Affinity Capture-MS), PCSK1 (Affinity Capture-MS), env (Biochemical Activity)

ESM2 similar proteins: A0A044RE18, B4F6N6, B5DF27, E1C3U7, F1QQC3, G5ECN9, O17798, O35548, O64481, P09231, P09958, P13134, P16519, P21661, P23188, P23377, P28840, P28841, P29119, P29120, P29122, P29145, P29146, P30432, P41413, P51512, P51559, P58022, P63239, P63240, P91863, Q03333, Q04592, Q08B63, Q09175, Q28193, Q5REC2, Q63415, Q8QGP3, Q8SQJ3

Diamond homologs: A0A044RE18, G5ECN9, O13359, O17798, P09231, P09958, P13134, P16519, P21661, P23188, P23377, P26016, P28840, P28841, P29119, P29120, P29121, P29122, P29141, P29145, P29146, P30430, P30432, P41413, P42781, P51559, P63239, P63240, P91863, Q03333, Q04592, Q09175, Q16549, Q28193, Q5REC2, Q61139, Q62849, Q63415, Q6UW60, Q78EH2

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
ATF1	“up-regulates quantity by expression”	PCSK1	“transcriptional regulation”
CREB1	“up-regulates quantity by expression”	PCSK1	“transcriptional regulation”
MAFA	“up-regulates quantity by expression”	PCSK1	“transcriptional regulation”
PAX6	“up-regulates quantity by expression”	PCSK1	“transcriptional regulation”
PCSK1	“up-regulates activity”	IAPP	cleavage
PCSK1	“up-regulates quantity”	Corticotropin	cleavage

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	2
Uncertain significance	21
Likely benign	10
Benign	1

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
1323428	NM_000439.5(PCSK1):c.958dup (p.Asp320fs)	Pathogenic
1723149	NM_000439.5(PCSK1):c.1095+1G>T	Pathogenic
2423087	NC_000005.9:g.(?95728705)(95765041_?)del	Pathogenic
1333251	NM_000439.5(PCSK1):c.1549C>T (p.Arg517Ter)	Likely pathogenic
3344148	NM_000439.5(PCSK1):c.1355dup (p.Leu452fs)	Likely pathogenic

SpliceAI

2004 predictions. Top by Δscore:

Variant	Effect	Δscore
5:96394865:T:TA	donor_gain	1.0000
5:96394866:C:A	donor_gain	1.0000
5:96394867:C:A	donor_gain	1.0000
5:96397470:C:CC	acceptor_gain	1.0000
5:96397471:T:C	acceptor_loss	1.0000
5:96398860:TAGA:T	donor_gain	1.0000
5:96398861:AGAA:A	donor_gain	1.0000
5:96398876:TACC:T	donor_loss	1.0000
5:96398877:A:AC	donor_gain	1.0000
5:96398877:A:G	donor_loss	1.0000
5:96398878:C:CC	donor_gain	1.0000
5:96398878:CCAG:C	donor_gain	1.0000
5:96398878:CCAGC:C	donor_loss	1.0000
5:96399032:GGGCT:G	acceptor_gain	1.0000
5:96399033:GGCT:G	acceptor_gain	1.0000
5:96399034:GCTC:G	acceptor_gain	1.0000
5:96399035:CT:C	acceptor_gain	1.0000
5:96399035:CTCT:C	acceptor_gain	1.0000
5:96399037:C:CC	acceptor_gain	1.0000
5:96399037:CTA:C	acceptor_loss	1.0000
5:96399041:A:AC	acceptor_gain	1.0000
5:96399041:A:C	acceptor_gain	1.0000
5:96399045:A:C	acceptor_gain	1.0000
5:96399949:TTA:T	donor_loss	1.0000
5:96399950:TACCT:T	donor_loss	1.0000
5:96399951:A:AC	donor_gain	1.0000
5:96399951:AC:A	donor_gain	1.0000
5:96399951:ACCT:A	donor_loss	1.0000
5:96399952:C:CG	donor_gain	1.0000
5:96399952:CC:C	donor_gain	1.0000

AlphaMissense

4979 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:96394971:C:A	G593W	1.000
5:96397405:C:A	W551C	1.000
5:96397405:C:G	W551C	1.000
5:96397407:A:G	W551R	1.000
5:96397407:A:T	W551R	1.000
5:96397433:T:A	D542V	1.000
5:96397433:T:G	D542A	1.000
5:96397434:C:G	D542H	1.000
5:96397441:T:A	R539S	1.000
5:96397441:T:G	R539S	1.000
5:96397442:C:A	R539I	1.000
5:96397442:C:G	R539T	1.000
5:96398905:A:G	L521P	1.000
5:96398911:C:A	G519V	1.000
5:96398911:C:T	G519E	1.000
5:96398913:T:A	R518S	1.000
5:96398913:T:G	R518S	1.000
5:96398914:C:G	R518T	1.000
5:96400064:C:T	G440E	1.000
5:96400066:A:C	F439L	1.000
5:96400066:A:T	F439L	1.000
5:96400068:A:G	F439L	1.000
5:96400105:C:A	W426C	1.000
5:96400105:C:G	W426C	1.000
5:96400107:A:G	W426R	1.000
5:96400107:A:T	W426R	1.000
5:96408250:C:T	G390D	1.000
5:96408262:G:T	P386H	1.000
5:96408268:G:A	S384F	1.000
5:96408268:G:T	S384Y	1.000

dbSNP variants (sampled 300 via entrez): RS1000047762 (5:96413134 T>C), RS1000103292 (5:96419818 T>A,C), RS1000112952 (5:96395764 C>T), RS1000235388 (5:96425698 C>A), RS1000241205 (5:96427592 C>T), RS1000344023 (5:96431717 A>T), RS1000460198 (5:96431334 T>C), RS1000514548 (5:96426136 C>CTAAA), RS1000563389 (5:96408685 G>T), RS1000747242 (5:96402108 T>G), RS1000760889 (5:96408980 C>T), RS1000837222 (5:96427272 A>G), RS1000889973 (5:96433606 AG>A,AGG), RS1000961578 (5:96393699 T>C), RS1001108161 (5:96421079 C>T)

Disease associations

OMIM: gene MIM:162150 | disease phenotypes: MIM:600955

GenCC curated gene-disease

Disease	Classification	Inheritance
obesity due to prohormone convertase I deficiency	Definitive	Autosomal recessive

Mondo (1): obesity due to prohormone convertase I deficiency (MONDO:0010961)

Orphanet (1): Obesity due to prohormone convertase I deficiency (Orphanet:71528)

HPO phenotypes

29 total (29 of 29 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000044	Hypogonadotropic hypogonadism
HP:0000786	Primary amenorrhea
HP:0000823	Delayed puberty
HP:0000824	Decreased response to growth hormone stimulation test
HP:0000842	Hyperinsulinemia
HP:0000956	Acanthosis nigricans
HP:0001010	Hypopigmentation of the skin
HP:0001396	Cholestasis
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001513	Obesity
HP:0002014	Diarrhea
HP:0002024	Malabsorption
HP:0002173	Hypoglycemic seizures
HP:0002297	Red hair
HP:0002591	Polyphagia
HP:0002750	Delayed skeletal maturation
HP:0008163	Decreased circulating cortisol level
HP:0008213	Gonadotropin deficiency
HP:0008245	Pituitary hypothyroidism
HP:0008915	Childhood-onset truncal obesity
HP:0009126	Increased adipose tissue
HP:0011463	Childhood onset
HP:0011473	Villous atrophy
HP:0011734	Central adrenal insufficiency
HP:0012051	Reactive hypoglycemia
HP:0040216	Hypoinsulinemia
HP:6000419	Elevated circulating proinsulin concentration

GWAS associations

20 associations (top):

Study	Trait	p-value
GCST001212_2	Proinsulin levels	1.000000e-26
GCST001415_3	Body mass index	5.000000e-09
GCST001527_5	Fasting blood glucose (BMI interaction)	2.000000e-10
GCST002110_6	Glycemic traits (pregnancy)	5.000000e-15
GCST002137_3	Waist circumference	1.000000e-06
GCST002461_21	Body mass index	8.000000e-13
GCST002541_13	Menarche (age at onset)	4.000000e-08
GCST002783_175	Body mass index	6.000000e-07
GCST002783_229	Body mass index	3.000000e-07
GCST004904_67	Body mass index	4.000000e-25
GCST005186_6	Fasting blood glucose	2.000000e-09
GCST006585_423	Blood protein levels	0.000000e+00
GCST007858_8	Fasting blood glucose adjusted for BMI	3.000000e-08
GCST008109_7	Fasting blood proinsulin levels	2.000000e-08
GCST008129_45	Body mass index	3.000000e-17
GCST009556_2	BMI at adiposity peak	2.000000e-06
GCST009863_5	Insulin-related traits (multivariate analysis)	8.000000e-32
GCST010118_46	Type 2 diabetes	3.000000e-09
GCST010988_335	Adult body size	2.000000e-09
GCST011332_2	Body mass index and fasting glucose (pairwise)	1.000000e-10

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004467	insulin measurement
EFO:0004340	body mass index
EFO:0004703	age at menarche
EFO:0005937	longitudinal BMI measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C563423	Proprotein Convertase 1 3 Deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3182 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — S8: Subtilisin

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
phenylacetyl-Arg-Val-Arg-4-amidinobenzylamide	Inhibition	9.12	pKi

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
9.12	Ki	0.75	nM	CHEMBL566340
8.77	Ki	1.7	nM	CHEMBL569918
8.70	Ki	2	nM	CHEMBL3126388
8.44	Ki	3.65	nM	CHEMBL568525
7.28	Ki	53	nM	CHEMBL569280
7.16	Ki	70	nM	CHEMBL568067

PubChem BioAssay actives

6 with measured affinity, of 6 total; 6 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
(2S)-N-[(2S)-1-[[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]-5-(diaminomethylideneamino)-2-[(2-phenylacetyl)amino]pentanamide	446389: Inhibition of human PC1/3 expressed in Drosophila schneider 2 cells by fluorescence assay	ki	0.0008	uM
(2S)-2-acetamido-N-[(2S)-1-[[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]-5-(diaminomethylideneamino)pentanamide	446389: Inhibition of human PC1/3 expressed in Drosophila schneider 2 cells by fluorescence assay	ki	0.0017	uM
137630787	1628273: Inhibition of recombinant C-terminal truncated human SPC3 expressed in drosophila Schneider 2 cells after 1 hr by spectrofluorometry	ki	0.0020	uM
N-[(2S)-1-[[(2S)-1-[[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]decanamide	446389: Inhibition of human PC1/3 expressed in Drosophila schneider 2 cells by fluorescence assay	ki	0.0037	uM
(2S)-5-(diaminomethylideneamino)-N-[(2S)-1-[[(2S)-5-(diaminomethylideneamino)-1-[4-(diaminomethylideneamino)butylamino]-1-oxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]-2-[(2-phenylacetyl)amino]pentanamide	446389: Inhibition of human PC1/3 expressed in Drosophila schneider 2 cells by fluorescence assay	ki	0.0530	uM
(2S)-N-[(2S)-1-[[(2S)-1-[(1-carbamimidoylpiperidin-4-yl)methylamino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]-5-(diaminomethylideneamino)-2-[(2-phenylacetyl)amino]pentanamide	446389: Inhibition of human PC1/3 expressed in Drosophila schneider 2 cells by fluorescence assay	ki	0.0700	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	5
bisphenol A	increases methylation, decreases expression, affects cotreatment	2
trichostatin A	increases expression	2
mercuric bromide	decreases expression, affects cotreatment	2
Nickel	increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
8-Bromo Cyclic Adenosine Monophosphate	increases expression	2
p-Chloromercuribenzoic Acid	decreases expression, affects cotreatment	2
arsenite	increases methylation	1
sulforaphane	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
clothianidin	decreases expression	1
abrine	increases expression	1
dorsomorphin	decreases expression, affects cotreatment	1
licochalcone B	decreases expression	1
(+)-JQ1 compound	decreases expression	1
imeglimin	increases expression	1
Temozolomide	decreases expression	1
Decitabine	affects expression	1
Arsenic Trioxide	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Gatifloxacin	increases expression	1
Aspirin	decreases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Doxorubicin	decreases expression	1
Estradiol	increases expression	1
Lipopolysaccharides	affects cotreatment, decreases 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
CHEMBL1049704	Binding	Inhibition of human PC1/3 expressed in Drosophila schneider 2 cells by fluorescence assay	Potent inhibitors of furin and furin-like proprotein convertases containing decarboxylated P1 arginine mimetics. — J Med Chem

Clinical trials (associated diseases)

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