PCSK5

Summary

PCSK5 (proprotein convertase subtilisin/kexin type 5, HGNC:8747) is a protein-coding gene on chromosome 9q21.13, encoding Proprotein convertase subtilisin/kexin type 5 (Q92824). Serine endoprotease that processes various proproteins by cleavage at paired basic amino acids, recognizing the RXXX[KR]R consensus motif.

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. It then sorts to the trans-Golgi network where a second autocatalytic event takes place and the catalytic activity is acquired. This encoded protein is widely expressed and one of the seven basic amino acid-specific members which cleave their substrates at single or paired basic residues. It mediates posttranslational endoproteolytic processing for several integrin alpha subunits and is thought to process prorenin, pro-membrane type-1 matrix metalloproteinase and HIV-1 glycoprotein gp160. Alternative splicing results in multiple transcript variants, some of which encode distinct isoforms, including a protease packaged into dense core granules (PC5A) and a type 1 membrane bound protease (PC5B).

Source: NCBI Gene 5125 — RefSeq curated summary.

At a glance

• Gene–disease (curated): syndromic congenital heart disease (Disputed, ClinGen)
• GWAS associations: 56
• Clinical variants (ClinVar): 160 total
• Druggable target: yes
• MANE Select transcript: NM_001372043

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8747
Approved symbol	PCSK5
Name	proprotein convertase subtilisin/kexin type 5
Location	9q21.13
Locus type	gene with protein product
Status	Approved
Aliases	PC5, PC6, SPC6
Ensembl gene	ENSG00000099139
Ensembl biotype	protein_coding
OMIM	600488
Entrez	5125

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 7 protein_coding, 1 retained_intron

ENST00000376752, ENST00000376767, ENST00000424854, ENST00000455778, ENST00000545128, ENST00000673745, ENST00000674117, ENST00000854198

RefSeq mRNA: 3 — MANE Select: NM_001372043 NM_001190482, NM_001372043, NM_006200

CCDS: CCDS55320, CCDS6652, CCDS94423

Canonical transcript exons

ENST00000674117 — 38 exons

Exon	Start	End
ENSE00000982907	76184673	76184757
ENSE00000982908	76188578	76188675
ENSE00000982909	76189094	76189223
ENSE00000982910	76189631	76189746
ENSE00001471558	76354033	76354219
ENSE00001471559	76350828	76350928
ENSE00001471560	76338230	76338447
ENSE00001471561	76332433	76332610
ENSE00001471563	76328009	76328239
ENSE00001471564	76323052	76323288
ENSE00001471565	76321422	76321639
ENSE00001471567	76310656	76310851
ENSE00001471568	76308645	76308728
ENSE00001471569	76302137	76302217
ENSE00001471570	76296665	76296865
ENSE00001471571	76295275	76295411
ENSE00001471572	76292233	76292275
ENSE00001471573	76240616	76240684
ENSE00001471574	76238959	76239165
ENSE00001471575	76233460	76233596
ENSE00001471576	76227503	76227605
ENSE00001592247	76158983	76159171
ENSE00001603422	76095890	76096102
ENSE00001630678	76067955	76068043
ENSE00001632782	76174986	76175129
ENSE00001642902	76107251	76107351
ENSE00001656200	76026961	76027037
ENSE00001668384	75932379	75932483
ENSE00001725017	76169704	76169840
ENSE00001754793	76157045	76157162
ENSE00001755345	75986132	75986245
ENSE00001756019	76023738	76023881
ENSE00001758986	76071726	76071898
ENSE00001765569	76134109	76134212
ENSE00001787378	76179596	76179698
ENSE00001799071	76181398	76181591
ENSE00001829437	75890673	75891373
ENSE00003896395	76358513	76362975

Expression profiles

Bgee: expression breadth ubiquitous, 264 present calls, max score 98.63.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.3135 / max 299.4091, expressed in 1350 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
96987	8.3571	1288
96986	0.9267	491
96993	0.0297	13

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	98.63	gold quality
saphenous vein	UBERON:0007318	96.16	gold quality
sural nerve	UBERON:0015488	94.64	gold quality
pericardium	UBERON:0002407	94.31	gold quality
pancreatic ductal cell	CL:0002079	92.18	gold quality
secondary oocyte	CL:0000655	91.09	gold quality
visceral pleura	UBERON:0002401	91.02	gold quality
mucosa of paranasal sinus	UBERON:0005030	90.82	gold quality
duodenum	UBERON:0002114	90.80	gold quality
parietal pleura	UBERON:0002400	90.28	gold quality
jejunal mucosa	UBERON:0000399	90.02	gold quality
blood vessel layer	UBERON:0004797	89.86	gold quality
pleura	UBERON:0000977	89.74	gold quality
urethra	UBERON:0000057	89.05	gold quality
germinal epithelium of ovary	UBERON:0001304	87.96	gold quality
amniotic fluid	UBERON:0000173	87.72	gold quality
mammalian vulva	UBERON:0000997	87.42	gold quality
bronchial epithelial cell	CL:0002328	87.03	gold quality
esophagus squamous epithelium	UBERON:0006920	86.72	gold quality
synovial joint	UBERON:0002217	86.44	gold quality
cervix squamous epithelium	UBERON:0006922	86.42	silver quality
nipple	UBERON:0002030	86.28	gold quality
epithelial cell of pancreas	CL:0000083	85.72	gold quality
cortical plate	UBERON:0005343	85.11	gold quality
oocyte	CL:0000023	85.00	gold quality
adipose tissue	UBERON:0001013	84.76	gold quality
tendon of biceps brachii	UBERON:0008188	84.75	gold quality
sperm	CL:0000019	84.68	gold quality
monocyte	CL:0000576	84.50	gold quality
epithelium of esophagus	UBERON:0001976	84.42	gold quality

Single-cell (SCXA)

Detected in 22 experiment(s), a significant marker in 14.

Experiment	Marker?	Max mean expression
E-MTAB-9067	yes	240044.53
E-GEOD-106540	yes	200956.04
E-CURD-97	yes	187644.24
E-GEOD-130473	yes	162996.09
E-MTAB-6678	yes	30455.82
E-MTAB-7381	yes	20481.86
E-GEOD-89232	yes	19684.01
E-CURD-6	yes	14563.48
E-GEOD-111727	yes	11892.58
E-CURD-10	yes	11450.52
E-MTAB-11268	yes	5395.86
E-MTAB-6379	yes	4144.07
E-GEOD-84465	yes	1862.17
E-ANND-3	yes	14.96
E-MTAB-7008	no	13965.59

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): PPARA

miRNA regulators (miRDB)

98 targeting PCSK5, 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-1252-5P	100.00	69.80	2774
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-4697-3P	99.89	67.09	1123
HSA-MIR-576-5P	99.84	70.46	2582

Literature-anchored findings (GeneRIF, showing 40)

• TTK69 is required for early (before the end of stage 4) repression of tll transcription. (PMID:12128207)
• Using neural repression as an assay, we dissected functional domains of Ttk, confirming the importance of the bric-a-brac-tramtrack-broad complex (BTB) motif. (PMID:12204250)
• directly regulates the transcription of string and thereby cell proliferation (PMID:12447387)
• identification of a novel allele of tramtrack (PMID:12490195)
• In different types of glial cells, REPO can act alone, or cooperate with either TTK69 or PNTP1 to regulate different target genes. (PMID:12702656)
• the binding of TTK69 prevents the interaction of GAGA with the transcription machinery and compromises its activation potential (PMID:14701830)
• Tramtrack downregulates Cyclin E expression and is probably involved in the exit of cells from the cell cycle. (PMID:15829522)
• A downstream target of Notch, tramtrack, acts at the mitotic-to-endocycle transition. JNK pathway is required to promote mitosis prior to the transition, independent of the cell cycle components acted on by the Notch pathway. (PMID:16542414)
• Results suggest that the involvement of Tramtrack in different steps of tube morphogenesis identifies it as a key player in tracheal development. (PMID:17881489)
• Sina protein may direct the degradation of the transcriptional repressor Tramtrack (Ttk) using two different mechanisms. (PMID:17962185)
• Deubiquitinylating enzyme UBP64 controls cell fate through stabilization of tkk. (PMID:18160715)
• Tramtrack (Ttk), a zinc-finger protein, is essential for the endocycle/gene amplification switch, is regulated negatively by Notch and positively by EcR. (PMID:18779369)
• Tramtrack69 (TTK69) controls the fates and shapes of all columnar follicle cells (PMID:19934014)
• Results lead to conclude that Ttk69 can either directly or indirectly repress lz gene expression to prevent the premature development of R7 precursor cells in the developing eye of Drosophila. (PMID:20003234)
• TTK69 is able to bind chromatin in the absence of NuRD, but targeting of NuRD is dependent on TTK69. (PMID:20733004)
• discovered multiple roles of Ttk in the development of the tracheal system on the morphogenetic level. Here, we sought to identify some of the underlying genetic components that are responsible for the tracheal phenotypes of Ttk mutants (PMID:22216153)
• The GBS two-component system CovS/CovR, which is the major acid response regulator in this organism, is required for survival inside the phagosome of macrophages. (PMID:22331428)
• Tramtrack69 functions as a developmental switch in Drosophila follicle cells where it is regulated by miR-7. (PMID:23325762)
• Ttk69 plays an instructive role in the growth of R7 photoreceptor axon terminals (PMID:23345225)
• Data indicate that tramtrack69 regulates ovary epithelial tube morphogenesis through Paxillin, Dynamin, and the homeobox protein Mirror. (PMID:23545328)
• The presence and timing of ttk69 expression are essential for somatic muscle development and required for the balance between founder cells and fusion-competent myoblasts. (PMID:24961800)
• Ttk69 acts as a master repressor of enteroendocrine cell specification in Drosophila intestinal stem cell lineages. (PMID:26293304)
• N activity is required to promote dpn transcription; only in R7 photoreceptor precursors does the removal of Ttk coincide with high N activity; and only in this cell does Dpn expression result (PMID:27427987)
• Ttk69 causes the histone deacetylation-mediated repression of tll via the interaction of Pits and Sin3A (PMID:27622813)
• Ttk69 plays a central role in shaping neural cell lineages . Ttk69 (1) promotes cell cycle exit of neural stem cells by downregulating CycE, and (2) regulates cell-fate acquisition and terminal differentiation, by downregulating the expression of hamlet and upregulating that of Suppressor of Hairless. (PMID:31073020)
• Drosophila miR-87 promotes dendrite regeneration by targeting the transcriptional repressor Tramtrack69. (PMID:32764744)
• TTK Isoforms Interact with Two Regions of the Mep-1 Protein of Drosophila melanogaster. (PMID:34189645)
• we investigated the specificity and potency of complete prodomains and short C-terminal prodomain peptides of each SPC on highly purified, soluble enzyme preparations of human SPC1, SPC6, and SPC7. (PMID:11723118)
• PC5/6 plays a key role for decidualization in human endometrium. (PMID:15522936)
• PC6 is an essential molecule in modulating uterine function to support the establishment of embryo implantation (PMID:15601911)
• furin and PC5 play a role in a MT-MMP-MMP-2 proteolytic cascade, involving provision of macrophage MT1-MMP for the activation of pro-MMP-2; furin and PC5 are expressed in monocytes and colocalize with MT1-MMP in macrophages in the atherosclerotic plaque (PMID:15911696)
• PCSK9 levels are finely regulated by the basic amino acid convertases furin and PC5/6A (PMID:16912035)
• in binding VEGFR-2, furin and PC5 promote cleavage of N-and C-terminal VEGF-D propeptides, whereas PC7 promotes cleavage of the C-terminal propeptide only (PMID:17242158)
• after stimulation, the protease activity of PC5A is enhanced, as evidenced by the cleavage of the PC5A substrates Lefty, ADAMTS-4, endothelial lipase, and PCSK9. (PMID:18039650)
• 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)
• fibrates simultaneously decreased PCSK9 expression while increasing PC5/6A and furin expression, indicating a broad action of PPARalpha activation in proprotein convertase-mediated lipid homeostasis. (PMID:18245819)
• We propose that Pcsk5, at least in part via GDF11, coordinately regulates caudal Hox paralogs, to control anteroposterior patterning, nephrogenesis, skeletal, and anorectal development. (PMID:18519639)
• Results describe the mechanisms of PC6 action in decidualization and identify caldesmon as one of its physiological substrates. (PMID:19764806)
• Variability at the PCSK5 locus influences high-density lipoprotein cholesterol levels. (PMID:20031622)
• The proteolytic activation and thus bioavailability of BMP2 is controlled by PC6. (PMID:20555025)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	pcsk5b	ENSDARG00000060518
mus_musculus	Pcsk5	ENSMUSG00000024713
rattus_norvegicus	Pcsk5	ENSRNOG00000012036

Paralogs (9): PCSK4 (ENSG00000115257), PCSK2 (ENSG00000125851), TPP2 (ENSG00000134900), PCSK6 (ENSG00000140479), FURIN (ENSG00000140564), MBTPS1 (ENSG00000140943), PCSK7 (ENSG00000160613), PCSK9 (ENSG00000169174), PCSK1 (ENSG00000175426)

Protein

Protein identifiers

Proprotein convertase subtilisin/kexin type 5 — Q92824 (reviewed: Q92824)

Alternative names: Proprotein convertase 5, Proprotein convertase 6, Subtilisin/kexin-like protease PC5

All UniProt accessions (5): Q92824, A0A669KA35, A0A669KBD8, B1AMG8, Q5JSG7

UniProt curated annotations — full annotation on UniProt →

Function. Serine endoprotease that processes various proproteins by cleavage at paired basic amino acids, recognizing the RXXX[KR]R consensus motif. Likely functions in the constitutive and regulated secretory pathways. Plays an essential role in pregnancy establishment by proteolytic activation of a number of important factors such as BMP2, CALD1 and alpha-integrins.

Subcellular location. Secreted Endomembrane system.

Tissue specificity. Expressed in T-lymphocytes.

Domain organisation. The propeptide domain acts as an intramolecular chaperone assisting the folding of the zymogen within the endoplasmic reticulum. AC 1 and AC 2 (clusters of acidic amino acids) contain sorting information. AC 1 directs TGN localization and interacts with the TGN sorting protein PACS-1.

Similarity. Belongs to the peptidase S8 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q92824-1	PC6B, Long	yes
Q92824-2	PC6A, Short

RefSeq proteins (3): NP_001177411, NP_001358972, NP_006191 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000209	Peptidase_S8/S53_dom	Domain
IPR000742	EGF	Domain
IPR002884	P_dom	Domain
IPR006212	Furin_repeat	Repeat
IPR008979	Galactose-bd-like_sf	Homologous_superfamily
IPR009030	Growth_fac_rcpt_cys_sf	Homologous_superfamily
IPR015500	Peptidase_S8_subtilisin-rel	Family
IPR022398	Peptidase_S8_His-AS	Active_site
IPR023827	Peptidase_S8_Asp-AS	Active_site
IPR023828	Peptidase_S8_Ser-AS	Active_site
IPR032778	GF_recep_IV	Domain
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, PF14843, PF16470

Enzyme classification (BRENDA):

• EC 3.4.21.B26 — (BRENDA: organisms, substrates, inhibitors, Km, kcat entries)

UniProt features (59 total): repeat 22, glycosylation site 12, sequence conflict 6, domain 3, region of interest 3, active site 3, topological domain 2, splice variant 2, signal peptide 1, propeptide 1, chain 1, short sequence motif 1, site 1, transmembrane region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92824-F1	76.31	0.18

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 (4): 171 (charge relay system); 212 (charge relay system); 386 (charge relay system); 114–115 (cleavage; by autolysis)

Glycosylation sites (12): 225, 381, 665, 752, 802, 852, 1014, 1191, 1290, 1497, 1685, 1707

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-167060	NGF processing
R-HSA-8963889	Assembly of active LPL and LIPC lipase complexes

MSigDB gene sets: 306 (showing top): GSE45365_NK_CELL_VS_BCELL_DN, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_REGULATION_OF_SYSTEMIC_ARTERIAL_BLOOD_PRESSURE_BY_CIRCULATORY_RENIN_ANGIOTENSIN, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_STEROL_HOMEOSTASIS, PEREZ_TP63_TARGETS, GOBP_EMBRYONIC_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_REGULATION_OF_SYSTEMIC_ARTERIAL_BLOOD_PRESSURE, GOBP_REGULATION_OF_HORMONE_LEVELS, RACCACAR_AML_Q6, TGACCTY_ERR1_Q2, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS

GO Biological Process (25): kidney development (GO:0001822), renin secretion into blood stream (GO:0002001), cell-cell signaling (GO:0007267), heart development (GO:0007507), embryo implantation (GO:0007566), anterior/posterior pattern specification (GO:0009952), protein processing (GO:0016485), peptide hormone processing (GO:0016486), viral life cycle (GO:0019058), respiratory tube development (GO:0030323), negative regulation of low-density lipoprotein particle receptor catabolic process (GO:0032804), plasma lipoprotein particle remodeling (GO:0034369), limb morphogenesis (GO:0035108), cholesterol homeostasis (GO:0042632), peptide biosynthetic process (GO:0043043), embryonic digestive tract development (GO:0048566), embryonic skeletal system development (GO:0048706), cytokine precursor processing (GO:0140447), cardiac septum development (GO:0003279), obsolete signal peptide processing (GO:0006465), proteolysis (GO:0006508), determination of left/right symmetry (GO:0007368), female pregnancy (GO:0007565), secretion by cell (GO:0032940), coronary vasculature development (GO:0060976)

GO Molecular Function (8): endopeptidase activity (GO:0004175), serine-type endopeptidase activity (GO:0004252), endopeptidase inhibitor activity (GO:0004866), peptidase activity (GO:0008233), peptide binding (GO:0042277), protein binding (GO:0005515), serine-type peptidase activity (GO:0008236), hydrolase activity (GO:0016787)

GO Cellular Component (8): Golgi membrane (GO:0000139), extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), Golgi apparatus (GO:0005794), Golgi lumen (GO:0005796), trans-Golgi network (GO:0005802), endomembrane system (GO:0012505), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Expression and Processing of Neurotrophins	1
Plasma lipoprotein remodeling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
animal organ development	3
cellular anatomical structure	3
signaling receptor ligand precursor processing	2
peptidase activity	2
endopeptidase activity	2
binding	2
Golgi apparatus	2
renal system development	1
renal response to blood flow involved in circulatory renin-angiotensin regulation of systemic arterial blood pressure	1
protein secretion	1
signal release	1
cell communication	1
signaling	1
circulatory system development	1
multicellular organism development	1
female pregnancy	1
reproductive process	1
regionalization	1
proteolysis	1
protein maturation	1
hormone metabolic process	1
viral process	1
tube development	1
low-density lipoprotein particle receptor catabolic process	1
regulation of low-density lipoprotein particle receptor catabolic process	1
negative regulation of protein catabolic process	1
negative regulation of receptor catabolic process	1
protein-lipid complex remodeling	1
plasma lipoprotein particle organization	1
regulation of plasma lipoprotein particle levels	1
appendage morphogenesis	1
limb development	1
sterol homeostasis	1
peptide metabolic process	1
biosynthetic process	1
digestive tract development	1
embryonic organ development	1
skeletal system development	1
chordate embryonic development	1
cytokine production	1

Protein interactions and networks

STRING

2137 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PCSK5	LIPN	Q5VXI9	891
PCSK5	PCSK9	Q8NBP7	868
PCSK5	MBTPS1	Q14703	753
PCSK5	GDF11	O95390	740
PCSK5	CD8A	P01732	735
PCSK5	KRT6B	P04259	723
PCSK5	SP6	Q3SY56	719
PCSK5	LRP5	O75197	671
PCSK5	PTPRC	P08575	630
PCSK5	NCAM1	P13591	613
PCSK5	CD4	P01730	612
PCSK5	CD19	P15391	610
PCSK5	ACRV1	P26436	595
PCSK5	MNX1	P50219	578
PCSK5	FCGR3A	P08637	571

IntAct

90 interactions, top by confidence:

A	B	Type	Score
IKBKG	IKBKB	psi-mi:“MI:0914”(association)	0.980
STK16	PCSK5	psi-mi:“MI:0915”(physical association)	0.560
PCSK5	GLRX3	psi-mi:“MI:0915”(physical association)	0.560
PCSK5	LCE3C	psi-mi:“MI:0915”(physical association)	0.560
PCSK5	NUFIP2	psi-mi:“MI:0915”(physical association)	0.560
PCSK5	MEOX2	psi-mi:“MI:0915”(physical association)	0.560
KRTAP5-9	PCSK5	psi-mi:“MI:0915”(physical association)	0.560
PCSK5	KRTAP10-7	psi-mi:“MI:0915”(physical association)	0.560
PCSK5	KRTAP10-8	psi-mi:“MI:0915”(physical association)	0.560
PCSK5		psi-mi:“MI:0915”(physical association)	0.560
PCSK5	NOTCH2NLA	psi-mi:“MI:0915”(physical association)	0.560
KRTAP4-12	PCSK5	psi-mi:“MI:0915”(physical association)	0.560
PCSK5	STK16	psi-mi:“MI:0915”(physical association)	0.560
NUFIP2	PCSK5	psi-mi:“MI:0915”(physical association)	0.560
MEOX2	PCSK5	psi-mi:“MI:0915”(physical association)	0.560
KRTAP10-7	PCSK5	psi-mi:“MI:0915”(physical association)	0.560
KRTAP10-8	PCSK5	psi-mi:“MI:0915”(physical association)	0.560
	PCSK5	psi-mi:“MI:0915”(physical association)	0.560
PCSK5	KRTAP4-12	psi-mi:“MI:0915”(physical association)	0.560
NOTCH2NLA	PCSK5	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (132): PCSK5 (Two-hybrid), PCSK5 (Two-hybrid), STK16 (Two-hybrid), GLRX3 (Two-hybrid), NUFIP2 (Two-hybrid), KRTAP4-12 (Two-hybrid), LCE3C (Two-hybrid), KRTAP10-7 (Two-hybrid), KRTAP10-8 (Two-hybrid), KRTAP10-3 (Two-hybrid), NOTCH2NL (Two-hybrid), PCSK5 (Affinity Capture-MS), PCSK5 (Affinity Capture-MS), PCSK5 (Affinity Capture-MS), PCSK5 (Affinity Capture-MS)

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

3 interactions.

A	Effect	B	Mechanism
PCSK5	“down-regulates quantity”	OXT	cleavage
PCSK5	“up-regulates quantity”	Oxytocin	cleavage
PCSK5	“up-regulates quantity”	“Neurophysin 1”	cleavage

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	99
Likely benign	17
Benign	16

Top pathogenic / likely-pathogenic (0)

SpliceAI

4406 predictions. Top by Δscore:

Variant	Effect	Δscore
9:75932364:A:AG	acceptor_gain	1.0000
9:75932365:C:G	acceptor_gain	1.0000
9:75932377:A:AG	acceptor_gain	1.0000
9:75932378:G:GG	acceptor_gain	1.0000
9:75932378:GATA:G	acceptor_gain	1.0000
9:75986126:TGACA:T	acceptor_loss	1.0000
9:75986127:GACA:G	acceptor_loss	1.0000
9:75986128:ACAGG:A	acceptor_loss	1.0000
9:75986129:CA:C	acceptor_loss	1.0000
9:76023736:A:AC	acceptor_loss	1.0000
9:76023736:A:AG	acceptor_gain	1.0000
9:76023737:G:GG	acceptor_gain	1.0000
9:76023737:GC:G	acceptor_gain	1.0000
9:76023737:GCACT:G	acceptor_gain	1.0000
9:76023877:ACTAC:A	donor_gain	1.0000
9:76023878:C:CG	donor_gain	1.0000
9:76023878:C:G	donor_gain	1.0000
9:76023879:TAC:T	donor_gain	1.0000
9:76023882:G:GG	donor_gain	1.0000
9:76023886:GT:G	donor_gain	1.0000
9:76026938:T:A	acceptor_gain	1.0000
9:76026950:T:TA	acceptor_gain	1.0000
9:76026952:T:TA	acceptor_gain	1.0000
9:76026953:G:A	acceptor_gain	1.0000
9:76026958:TA:T	acceptor_loss	1.0000
9:76026959:A:AC	acceptor_loss	1.0000
9:76026959:A:AG	acceptor_gain	1.0000
9:76026960:G:GG	acceptor_gain	1.0000
9:76027038:G:GG	donor_gain	1.0000
9:76071721:TGAA:T	acceptor_loss	1.0000

AlphaMissense

12604 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:75891296:T:A	W39R	1.000
9:75891296:T:C	W39R	1.000
9:75986227:G:C	W131C	1.000
9:75986227:G:T	W131C	1.000
9:75986237:T:A	W135R	1.000
9:75986237:T:C	W135R	1.000
9:75986239:G:C	W135C	1.000
9:75986239:G:T	W135C	1.000
9:76023792:T:A	W156R	1.000
9:76023792:T:C	W156R	1.000
9:76023794:G:C	W156C	1.000
9:76023794:G:T	W156C	1.000
9:76023810:G:A	G162R	1.000
9:76023810:G:C	G162R	1.000
9:76023811:G:A	G162E	1.000
9:76023826:T:A	V167D	1.000
9:76023832:T:A	I169N	1.000
9:76023835:T:C	L170P	1.000
9:76023837:G:C	D171H	1.000
9:76023837:G:T	D171Y	1.000
9:76023838:A:C	D171A	1.000
9:76023838:A:T	D171V	1.000
9:76023839:T:A	D171E	1.000
9:76023839:T:G	D171E	1.000
9:76023840:G:C	D172H	1.000
9:76023840:G:T	D172Y	1.000
9:76023841:A:C	D172A	1.000
9:76023841:A:G	D172G	1.000
9:76023841:A:T	D172V	1.000
9:76023842:C:A	D172E	1.000

dbSNP variants (sampled 300 via entrez): RS1000000011 (9:76228713 G>A), RS1000006599 (9:76045598 T>C), RS1000007824 (9:76183610 A>G), RS1000010495 (9:75891538 C>A), RS1000010709 (9:75970463 C>G), RS1000014247 (9:76003765 G>T), RS1000014255 (9:76345465 C>G,T), RS1000015372 (9:76089947 A>G), RS1000027844 (9:76013131 TA>T), RS1000030655 (9:75919945 A>G), RS1000043401 (9:76314495 G>A), RS1000047603 (9:76145968 C>A), RS1000057132 (9:76264888 A>G), RS1000060567 (9:76134486 T>G), RS1000061151 (9:76102888 T>C)

Disease associations

OMIM: gene MIM:600488 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
syndromic congenital heart disease	Disputed Evidence	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
syndromic congenital heart disease	Disputed	AD

Mondo (1): syndromic congenital heart disease (MONDO:0100614)

Orphanet (0):

HPO phenotypes

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

GWAS associations

56 associations (top):

Study	Trait	p-value
GCST000817_103	Height	1.000000e-11
GCST000892_7	Total ventricular volume (Alzheimer’s disease interaction)	3.000000e-06
GCST001540_5	Male fertility	6.000000e-06
GCST001663_12	Amyotrophic lateral sclerosis (age of onset)	7.000000e-06
GCST001738_8	Response to fenofibrate (adiponectin levels)	1.000000e-06
GCST001820_6	Metabolite levels (5-HIAA)	5.000000e-06
GCST001956_49	Height	4.000000e-16
GCST002590_11	Vascular brain injury	3.000000e-06
GCST002590_3	Vascular brain injury	2.000000e-06
GCST002647_28	Height	6.000000e-24
GCST002726_15	Glucose homeostasis traits	3.000000e-06
GCST002935_16	Lead levels	6.000000e-06
GCST003084_4	Glucocorticoid-induced osteonecrosis	3.000000e-06
GCST003602_6	Inflammatory bowel disease	7.000000e-06
GCST004063_140	Waist circumference adjusted for body mass index	2.000000e-08
GCST004500_31	Waist circumference adjusted for BMI (adjusted for smoking behaviour)	4.000000e-06
GCST004501_121	Waist circumference adjusted for BMI (joint analysis main effects and smoking interaction)	5.000000e-06
GCST004504_89	Waist circumference adjusted for BMI in non-smokers	1.000000e-06
GCST005024_78	Pursuit maintenance gain	3.000000e-06
GCST006136_9	Alzheimer’s disease progression score	4.000000e-06
GCST006394_23	Intraocular pressure	4.000000e-09
GCST006412_106	Intraocular pressure	1.000000e-10
GCST006479_140	Diverticular disease	2.000000e-08
GCST006493_11	Systemic sclerosis	9.000000e-06
GCST006575_52	Takayasu arteritis	9.000000e-07
GCST007294_132	Body fat distribution (trunk fat ratio)	2.000000e-31
GCST007294_158	Body fat distribution (trunk fat ratio)	8.000000e-24
GCST007295_125	Body fat distribution (leg fat ratio)	5.000000e-27
GCST007295_168	Body fat distribution (leg fat ratio)	2.000000e-20
GCST007844_5	Ankylosing spondylitis	6.000000e-06

EFO canonical traits (19, from GWAS)

EFO ID	Trait name
EFO:0004802	family size
EFO:0004803	male fertility
EFO:0004847	age at onset
EFO:0005132	5-HIAA measurement
EFO:0006800	vascular brain injury measurement
EFO:0004471	insulin sensitivity measurement
EFO:0007789	BMI-adjusted waist circumference
EFO:0004318	smoking behavior
EFO:0008433	pursuit maintenance gain measurement
EFO:0006514	Alzheimer’s disease biomarker measurement
EFO:0004695	intraocular pressure measurement
EFO:0009959	diverticular disease
EFO:0004341	body fat distribution
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004329	alcohol drinking
EFO:0004615	apolipoprotein B measurement
EFO:0004338	body weight
EFO:0008039	BMI-adjusted hip circumference
EFO:0007788	BMI-adjusted waist-hip ratio

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2826 (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 (2 total), top 2:

Ligand	Action	Affinity	Parameter
phenylacetyl-Arg-Val-Arg-4-amidinobenzylamide	Inhibition	8.8	pKi
furin inhibitor peptide	Inhibition	6.63	pKi

ChEMBL bioactivities

12 potent at pChembl≥5 of 12 total, top 12 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.92	Ki	0.12	nM	CHEMBL3126388
8.80	Ki	1.6	nM	CHEMBL566340
8.44	Ki	3.6	nM	CHEMBL569918
8.20	Ki	6.3	nM	CHEMBL568525
7.07	Ki	85	nM	CHEMBL569280
6.76	Ki	173	nM	CHEMBL568067
6.73	Ki	188	nM	CHEMBL455792
6.63	Ki	232	nM	CHEMBL502642
6.36	Ki	433	nM	CHEMBL503520
6.31	Ki	492	nM	CHEMBL525748
6.19	Ki	649	nM	CHEMBL499438
6.09	Ki	806	nM	CHEMBL500184

PubChem BioAssay actives

12 with measured affinity, of 16 total; 12 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
137630787	1628275: Inhibition of recombinant C-terminal truncated human SPC6 expressed in drosophila Schneider 2 cells after 1 hr by spectrofluorometry	ki	0.0001	uM
(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	446387: Inhibition of human PC5/6 expressed in Drosophila schneider 2 cells by fluorescence assay	ki	0.0016	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	446387: Inhibition of human PC5/6 expressed in Drosophila schneider 2 cells by fluorescence assay	ki	0.0036	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	446387: Inhibition of human PC5/6 expressed in Drosophila schneider 2 cells by fluorescence assay	ki	0.0063	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	446387: Inhibition of human PC5/6 expressed in Drosophila schneider 2 cells by fluorescence assay	ki	0.0850	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	446387: Inhibition of human PC5/6 expressed in Drosophila schneider 2 cells by fluorescence assay	ki	0.1730	uM
(2S,3R)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-1-[(2S,3R)-2-amino-3-hydroxybutanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]propanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]hexanoyl]amino]hexanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-3-hydroxybutanoic acid	360137: Inhibition of human recombinant PC5/6 assessed as fluorescent Pyr-RTKR-AMC substrate cleavage	ki	0.1880	uM
(2S)-N-[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxohexan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-1-[(2S,3R)-2-amino-3-hydroxybutanoyl]pyrrolidine-2-carboxamide	360137: Inhibition of human recombinant PC5/6 assessed as fluorescent Pyr-RTKR-AMC substrate cleavage	ki	0.2320	uM
(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-1-[(2S,3R)-2-amino-3-hydroxybutanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]propanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]hexanoyl]amino]hexanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-3-(1H-indol-3-yl)propanoic acid	360137: Inhibition of human recombinant PC5/6 assessed as fluorescent Pyr-RTKR-AMC substrate cleavage	ki	0.4330	uM
(2S)-N-[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S,3S)-1-amino-3-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxohexan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-1-[(2S,3R)-2-amino-3-hydroxybutanoyl]pyrrolidine-2-carboxamide	360137: Inhibition of human recombinant PC5/6 assessed as fluorescent Pyr-RTKR-AMC substrate cleavage	ki	0.4920	uM
(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-1-[(2S,3R)-2-amino-3-hydroxybutanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]propanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]hexanoyl]amino]hexanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-3-(4-hydroxyphenyl)propanoic acid	360137: Inhibition of human recombinant PC5/6 assessed as fluorescent Pyr-RTKR-AMC substrate cleavage	ki	0.6490	uM
(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-1-[(2S,3R)-2-amino-3-hydroxybutanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]propanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]hexanoyl]amino]hexanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-3-phenylpropanoic acid	360137: Inhibition of human recombinant PC5/6 assessed as fluorescent Pyr-RTKR-AMC substrate cleavage	ki	0.8060	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tetrachlorodibenzodioxin	affects expression, decreases expression, increases expression	7
Benzo(a)pyrene	affects methylation, decreases expression, increases expression, increases mutagenesis	5
trichostatin A	decreases expression, affects cotreatment	3
Valproic Acid	affects expression, increases expression	3
entinostat	decreases expression, affects cotreatment	2
Arsenic Trioxide	decreases expression, increases expression	2
Cyclosporine	increases expression	2
Aflatoxin B1	affects methylation, decreases methylation	2
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
beta-lapachone	decreases expression	1
butyraldehyde	decreases expression	1
9,10-dihydro-9,10-dihydroxybenzo(a)pyrene	increases expression	1
3,4,5,3’,4’-pentachlorobiphenyl	increases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	decreases methylation	1
di-n-butylphosphoric acid	affects expression	1
perfluoro-n-nonanoic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	decreases methylation	1
(+)-JQ1 compound	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	affects expression, increases abundance	1
Benzene	decreases expression	1
Cytarabine	decreases expression	1
Diazinon	increases methylation	1

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1008224	Binding	Inhibition of human recombinant PC5/6 assessed as fluorescent Pyr-RTKR-AMC substrate cleavage	Targeting host cell furin proprotein convertases as a therapeutic strategy against bacterial toxins and viral pathogens. — J Biol Chem

Clinical trials (associated diseases)

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