PCSK6 (proprotein convertase subtilisin/kexin type 6)

Gene

• Entrez ID: 5046
• Gene name: Proprotein convertase subtilisin/kexin type 6
• Gene symbol: PCSK6
• Synonyms (NCBI Gene): PACE4, SPC4
• Chromosome: 15
• Chromosome location: 15q26.3
• Summary: 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 under

miRNA

miRTarBase ID	miRNA	Experiments	Reference
MIRT039239	hsa-miR-454-3p	CLASH	23622248
MIRT701011	hsa-miR-302f	HITS-CLIP	23313552
MIRT701010	hsa-miR-6782-3p	HITS-CLIP	23313552
MIRT701009	hsa-miR-3190-5p	HITS-CLIP	23313552
MIRT701008	hsa-miR-219b-3p	HITS-CLIP	23313552
MIRT701007	hsa-miR-4529-5p	HITS-CLIP	23313552
MIRT701006	hsa-miR-3652	HITS-CLIP	23313552
MIRT701005	hsa-miR-4430	HITS-CLIP	23313552
MIRT701004	hsa-miR-4505	HITS-CLIP	23313552
MIRT701003	hsa-miR-5787	HITS-CLIP	23313552
MIRT701002	hsa-miR-1273e	HITS-CLIP	23313552
MIRT701001	hsa-miR-548s	HITS-CLIP	23313552
MIRT701000	hsa-miR-4701-5p	HITS-CLIP	23313552
MIRT700999	hsa-miR-588	HITS-CLIP	23313552
MIRT700998	hsa-miR-4435	HITS-CLIP	23313552
MIRT700997	hsa-miR-3187-3p	HITS-CLIP	23313552
MIRT700996	hsa-miR-647	HITS-CLIP	23313552
MIRT700995	hsa-miR-6842-3p	HITS-CLIP	23313552
MIRT701011	hsa-miR-302f	HITS-CLIP	23313552
MIRT701010	hsa-miR-6782-3p	HITS-CLIP	23313552
MIRT701009	hsa-miR-3190-5p	HITS-CLIP	23313552
MIRT701008	hsa-miR-219b-3p	HITS-CLIP	23313552
MIRT701007	hsa-miR-4529-5p	HITS-CLIP	23313552
MIRT701006	hsa-miR-3652	HITS-CLIP	23313552
MIRT701005	hsa-miR-4430	HITS-CLIP	23313552
MIRT701004	hsa-miR-4505	HITS-CLIP	23313552
MIRT701003	hsa-miR-5787	HITS-CLIP	23313552
MIRT701002	hsa-miR-1273e	HITS-CLIP	23313552
MIRT701001	hsa-miR-548s	HITS-CLIP	23313552
MIRT701000	hsa-miR-4701-5p	HITS-CLIP	23313552
MIRT700999	hsa-miR-588	HITS-CLIP	23313552
MIRT700998	hsa-miR-4435	HITS-CLIP	23313552
MIRT700997	hsa-miR-3187-3p	HITS-CLIP	23313552
MIRT700996	hsa-miR-647	HITS-CLIP	23313552
MIRT700995	hsa-miR-6842-3p	HITS-CLIP	23313552
MIRT1218527	hsa-miR-1271	CLIP-seq
MIRT1218528	hsa-miR-182	CLIP-seq
MIRT1218529	hsa-miR-21	CLIP-seq
MIRT1218530	hsa-miR-3163	CLIP-seq
MIRT1218531	hsa-miR-340	CLIP-seq
MIRT1218532	hsa-miR-3662	CLIP-seq
MIRT1218533	hsa-miR-4464	CLIP-seq
MIRT1218534	hsa-miR-4672	CLIP-seq
MIRT1218535	hsa-miR-4748	CLIP-seq
MIRT1218536	hsa-miR-4773	CLIP-seq
MIRT1218537	hsa-miR-548c-3p	CLIP-seq
MIRT1218538	hsa-miR-590-5p	CLIP-seq
MIRT1218539	hsa-miR-96	CLIP-seq
MIRT1218540	hsa-miR-103a	CLIP-seq
MIRT1218541	hsa-miR-107	CLIP-seq
MIRT1218542	hsa-miR-15a	CLIP-seq
MIRT1218543	hsa-miR-15b	CLIP-seq
MIRT1218544	hsa-miR-16	CLIP-seq
MIRT1218545	hsa-miR-195	CLIP-seq
MIRT1218546	hsa-miR-424	CLIP-seq
MIRT1218547	hsa-miR-4310	CLIP-seq
MIRT1218548	hsa-miR-497	CLIP-seq
MIRT1218549	hsa-miR-3920	CLIP-seq
MIRT1218550	hsa-miR-3921	CLIP-seq
MIRT1218551	hsa-miR-4653-5p	CLIP-seq
MIRT1218552	hsa-miR-4768-5p	CLIP-seq
MIRT1218553	hsa-miR-146a	CLIP-seq
MIRT1218554	hsa-miR-146b-5p	CLIP-seq
MIRT1218555	hsa-miR-218	CLIP-seq
MIRT1218530	hsa-miR-3163	CLIP-seq
MIRT1218532	hsa-miR-3662	CLIP-seq
MIRT1218556	hsa-miR-3908	CLIP-seq
MIRT1218557	hsa-miR-3910	CLIP-seq
MIRT1218558	hsa-miR-3942-5p	CLIP-seq
MIRT1218559	hsa-miR-4703-5p	CLIP-seq
MIRT1218560	hsa-miR-4766-3p	CLIP-seq
MIRT1218536	hsa-miR-4773	CLIP-seq
MIRT1218561	hsa-miR-589	CLIP-seq
MIRT1218562	hsa-miR-636	CLIP-seq
MIRT2439230	hsa-miR-375	CLIP-seq
MIRT2439231	hsa-miR-4320	CLIP-seq
MIRT2439232	hsa-miR-4326	CLIP-seq
MIRT2439233	hsa-miR-4760-3p	CLIP-seq
MIRT2439234	hsa-miR-579	CLIP-seq
MIRT2439235	hsa-miR-664	CLIP-seq
MIRT2439230	hsa-miR-375	CLIP-seq
MIRT2439231	hsa-miR-4320	CLIP-seq
MIRT2439232	hsa-miR-4326	CLIP-seq
MIRT2439233	hsa-miR-4760-3p	CLIP-seq
MIRT2439234	hsa-miR-579	CLIP-seq
MIRT2439235	hsa-miR-664	CLIP-seq

Transcription factors

Transcription factor	Regulation	Reference
ASCL1	Repression	11736660
E2F1	Activation	17825503

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0004175	Function	Endopeptidase activity	IDA	9242664
GO:0004175	Function	Endopeptidase activity	TAS
GO:0004252	Function	Serine-type endopeptidase activity	IBA
GO:0004252	Function	Serine-type endopeptidase activity	IDA	8218226, 8615794, 8906861
GO:0004252	Function	Serine-type endopeptidase activity	IEA
GO:0005515	Function	Protein binding	IPI	16433634, 32296183
GO:0005576	Component	Extracellular region	IEA
GO:0005576	Component	Extracellular region	TAS
GO:0005615	Component	Extracellular space	IBA
GO:0005615	Component	Extracellular space	IDA	8906861
GO:0005783	Component	Endoplasmic reticulum	IEA
GO:0005796	Component	Golgi lumen	TAS
GO:0005886	Component	Plasma membrane	TAS
GO:0006508	Process	Proteolysis	IEA
GO:0007354	Process	Zygotic determination of anterior/posterior axis, embryo	IEA
GO:0007368	Process	Determination of left/right symmetry	IEA
GO:0008201	Function	Heparin binding	IDA	12535616
GO:0008233	Function	Peptidase activity	IEA
GO:0008236	Function	Serine-type peptidase activity	IEA
GO:0009100	Process	Glycoprotein metabolic process	IDA	8218226
GO:0009986	Component	Cell surface	IBA
GO:0009986	Component	Cell surface	IDA	12535616
GO:0012505	Component	Endomembrane system	IEA
GO:0016020	Component	Membrane	IBA
GO:0016020	Component	Membrane	IEA
GO:0016485	Process	Protein processing	IDA	8218226, 9242664, 9738469
GO:0016485	Process	Protein processing	IEA
GO:0016486	Process	Peptide hormone processing	IBA
GO:0016486	Process	Peptide hormone processing	IDA	9242664
GO:0016486	Process	Peptide hormone processing	IEA
GO:0016787	Function	Hydrolase activity	IEA
GO:0030510	Process	Regulation of BMP signaling pathway	TAS	10467177
GO:0031012	Component	Extracellular matrix	IBA
GO:0031012	Component	Extracellular matrix	IDA	12535616
GO:0032902	Process	Nerve growth factor production	IDA	8615794
GO:0032940	Process	Secretion by cell	IDA	8615794
GO:0032940	Process	Secretion by cell	IEA
GO:0034369	Process	Plasma lipoprotein particle remodeling	IEA
GO:0034369	Process	Plasma lipoprotein particle remodeling	TAS
GO:0048406	Function	Nerve growth factor binding	IDA	8615794

Other IDs

• MIM: 167405
• HGNC: 8569
• e!Ensembl: ENSG00000140479

Protein

• UniProt ID: P29122
• Protein name: Proprotein convertase subtilisin/kexin type 6 (EC 3.4.21.-) (Paired basic amino acid cleaving enzyme 4) (Subtilisin-like proprotein convertase 4) (SPC4) (Subtilisin/kexin-like protease PACE4)
• Protein 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 secretory pathway, with unique restricted distribution in both neuroe
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF16470	S8_pro-domain	73 → 149	Peptidase S8 pro-domain	Domain
  PF00082	Peptidase_S8	196 → 479	Subtilase family	Domain
  PF01483	P_proprotein	539 → 629	Proprotein convertase P-domain	Family
  PF14843	GF_recep_IV	694 → 812	Growth factor receptor domain IV	Domain
  PF08686	PLAC	935 → 966	PLAC (protease and lacunin) domain	Domain

• Tissue specificity: TISSUE SPECIFICITY: Each PACE4 isoform exhibits a unique restricted distribution. Isoform PACE4A-I is expressed in heart, brain, placenta, lung, skeletal muscle, kidney, pancreas, but at comparatively higher levels in the liver. Isoform PACE4A-II is at le
• Sequence:

  MPPRAPPAPGPRPPPRAAAATDTAAGAGGAGGAGGAGGPGFRPLAPRPWRWLLLLALPAA
  CSAPPPRPVYTNHWAVQVLGGPAEADRVAAAHGYLNLGQIGNLEDYYHFYHSKTFKRSTL
  SSRGPHTFLRMDPQVKWLQQQEVKRRVKRQVRSDPQALYFNDPIWSNMWYLHCGDKNSRC
  RSEMNVQAAWKRGYTGKNVVVTILDDGIERNHPDLAPNYDSYASYDVNGNDYDPSPRYDA
  SNENKHGTRCAGEVAASANNSYCIVGIAYNAKIGGIRMLDGDVTDVVEAKSLGIRPNYID
  IYSASWGPDDDGKTVDGPGRLAKQAFEYGIKKGRQGLGSIFVWASGNGGREGDYCSCDGY
  TNSIYTISVSSATENGYKPWYLEECASTLATTYSSGAFYERKIVTTDLRQRCTDGHTGTS
  VSAPMVAGIIALALEANSQLTWRDVQHLLVKTSRPAHLKASDWKVNGAGHKVSHFYGFGL
  VDAEALVVEAKKWTAVPSQHMCVAASDKRPRSIPLVQVLRTTALTSACAEHSDQRVVYLE
  HVVVRTSISHPRRGDLQIYLVSPSGTKSQLLAKRLLDLSNEGFTNWEFMTVHCWGEKAEG
  QWTLEIQDLPSQVRNPEKQGKLKEWSLILYGTAEHPYHTFSAHQSRSRMLELSAPELEPP
  KAALSPSQVEVPEDEEDYTAQSTPGSANILQTSVCHPECGDKGCDGPNADQCLNCVHFSL
  GSVKTSRKCVSVCPLGYFGDTAARRCRRCHKGCETCSSRAATQCLSCRRGFYHHQEMNTC
  VTLCPAGFYADESQKNCLKCHPSCKKCVDEPEKCTVCKEGFSLARGSCIPDCEPGTYFDS
  ELIRCGECHHTCGTCVGPGREECIHCAKNFHFHDWKCVPACGEGFYPEEMPGLPHKVCRR
  CDENCLSCAGSSRNCSRCKTGFTQLGTSCITNHTCSNADETFCEMVKSNRLCERKLFIQF
  CCRTCLLAG

• Sequence length: 969

Pathways

Reactome:

NGF processing
Formation of the cornified envelope
Assembly of active LPL and LIPC lipase complexes

Associated diseases

Evidence Score:

• ★☆☆☆☆  Gene-disease association found in Text Mining only
• ★★☆☆☆  Found in Text Mining and Unknown/Other Associations
• ★★★☆☆  Reported in Unknown/Other Associations across ≥2 Sources
• ★★★★☆  ClinVar: Pathogenic/Likely Pathogenic (<5 Variants)
• ★★★★★  ClinVar: Pathogenic/Likely Pathogenic (≥5 Variants)

Unknown / Other Associations
Phenotype Name	Clinical Significance	Source	Evidence Score
CARDIAC EMBOLISM	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
CARDIOEMBOLIC STROKE	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
CONGENITAL HEART DISEASE	—	Disgenet	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
CORONARY STENOSIS	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
DIABETIC NEPHROPATHY	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
IDIOPATHIC PULMONARY FIBROSIS	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
LATE-ONSET ALZHEIMER'S DISEASE	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
MAJOR DEPRESSIVE DISORDER	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
PERIPHERAL ARTERIAL DISEASE	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
SCOLIOSIS	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
TYPE 2 DIABETES MELLITUS	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
UPPER AERODIGESTIVE TRACT NEOPLASM	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Uterine carcinosarcoma	Benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Uterine corpus endometrial carcinoma	Benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Uveal melanoma	Likely benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
WET MACULAR DEGENERATION	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations

Associations from Text Mining
Disease Name	Disease (Merged)	Source	PMID	Relationship Type	Evidence Score
Arteriosclerosis	Arteriosclerosis	BEFREE	23908247, 30781751		★☆☆☆☆ Found in Text Mining only
Arthritis Rheumatoid	Rheumatoid arthritis	Pubtator	37149637	Associate	★☆☆☆☆ Found in Text Mining only
Atherosclerosis	Atherosclerosis	BEFREE	23908247, 30781751		★☆☆☆☆ Found in Text Mining only
Atherosclerosis	Atherosclerosis	Pubtator	33359561	Associate	★☆☆☆☆ Found in Text Mining only
Atrial Septal Defects	Atrial Septal Defect	BEFREE	26744331		★☆☆☆☆ Found in Text Mining only
Autistic Disorder	Autism	BEFREE	26921480		★☆☆☆☆ Found in Text Mining only
Breast Carcinoma	Breast Carcinoma	BEFREE	17909005, 25333574, 28347547, 29928395, 9185698		★☆☆☆☆ Found in Text Mining only
Carcinoma Squamous Cell	Squamous cell carcinoma	Pubtator	9166946	Associate	★☆☆☆☆ Found in Text Mining only
Carcinoma, Ovarian Epithelial	Ovarian Epithelial carcinoma	BEFREE	12805404, 21805246		★☆☆☆☆ Found in Text Mining only
Carotid Atherosclerosis	Carotid Atherosclerosis	BEFREE	23908247		★☆☆☆☆ Found in Text Mining only
Congestive heart failure	Congestive Heart Failure	BEFREE	29774097, 30781751		★☆☆☆☆ Found in Text Mining only
Coronary Artery Disease	Coronary artery disease	BEFREE	31825978		★☆☆☆☆ Found in Text Mining only
Coronary heart disease	Coronary Heart Disease	BEFREE	26744331		★☆☆☆☆ Found in Text Mining only
Degenerative polyarthritis	Arthritis	BEFREE	22440827		★☆☆☆☆ Found in Text Mining only
Diabetes Mellitus, Non-Insulin-Dependent	Diabetes Mellitus	GWASCAT_DG	30470734		★☆☆☆☆ Found in Text Mining only
Dyslexia	Dyslexia	BEFREE	21051773, 26908617		★☆☆☆☆ Found in Text Mining only
Dyslexia	Dyslexia	GWASCAT_DG	21051773, 24068947		★☆☆☆☆ Found in Text Mining only
Dyslexia	Dyslexia	Pubtator	21051773, 26908617	Associate	★☆☆☆☆ Found in Text Mining only
Endometrial Carcinoma	Endometrial carcinoma	BEFREE	22390935		★☆☆☆☆ Found in Text Mining only
Glioblastoma	Glioblastoma	BEFREE	21722156		★☆☆☆☆ Found in Text Mining only
Glioblastoma Multiforme	Glioblastoma	BEFREE	21722156		★☆☆☆☆ Found in Text Mining only
Glioma	Glioma	BEFREE	21722156		★☆☆☆☆ Found in Text Mining only
Heart Defects Congenital	Congenital heart defect	Pubtator	23705960	Associate	★☆☆☆☆ Found in Text Mining only
Heart failure	Heart Failure	BEFREE	29774097, 30781751		★☆☆☆☆ Found in Text Mining only
Hypertensive disease	Hypertension	BEFREE	26259032, 30781751		★☆☆☆☆ Found in Text Mining only
Idiopathic Pulmonary Fibrosis	Idiopathic pulmonary fibrosis	Pubtator	36780644	Associate	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Immunologic Deficiency Syndromes	Immunologic Deficiency Syndromes	BEFREE	24318887		★☆☆☆☆ Found in Text Mining only
Leukemia, Myelocytic, Acute	Leukemia	GWASCAT_DG	27903959		★☆☆☆☆ Found in Text Mining only
Lung Neoplasms	Lung neoplasms	Pubtator	23409034, 9166946	Associate	★☆☆☆☆ Found in Text Mining only
Malignant Glioma	Glioma	BEFREE	21722156		★☆☆☆☆ Found in Text Mining only
Malignant neoplasm of breast	Breast Cancer	BEFREE	17909005, 25333574, 28347547, 29928395, 9185698		★☆☆☆☆ Found in Text Mining only
Malignant neoplasm of endometrium	Endometrial Cancer	BEFREE	22390935		★☆☆☆☆ Found in Text Mining only
Malignant neoplasm of ovary	Ovarian cancer	BEFREE	12805404, 21805246		★☆☆☆☆ Found in Text Mining only
Malignant neoplasm of pancreas	Pancreatic cancer	BEFREE	27779720		★☆☆☆☆ Found in Text Mining only
Malignant neoplasm of prostate	Prostate cancer	BEFREE	23226097, 24318887, 24913567, 26114115, 26604689, 27779720, 28287731, 28347547, 28456517, 28483279, 28722823, 28993410, 30180568, 30501188, 30765725		★☆☆☆☆ Found in Text Mining only
Malignant Neoplasms	Malignant Neoplasm	BEFREE	22390935, 24913567, 28993410, 29928395, 30180568		★☆☆☆☆ Found in Text Mining only
Mammary Neoplasms	Mammary Neoplasms	LHGDN	17909005		★☆☆☆☆ Found in Text Mining only
Mouth Neoplasms	Mouth neoplasm	Pubtator	35410344	Associate	★☆☆☆☆ Found in Text Mining only
Neoplasms	Neoplasms	BEFREE	23226097, 23441131, 24318887, 26114115, 29928395, 30765725		★☆☆☆☆ Found in Text Mining only
Neuroblastoma	Neuroblastoma	BEFREE	11736660		★☆☆☆☆ Found in Text Mining only
Neuroblastoma	Neuroblastoma	Pubtator	11736660	Associate	★☆☆☆☆ Found in Text Mining only
Oestrogen receptor positive breast cancer	Oestrogen Receptor Positive Breast Cancer	BEFREE	28347547		★☆☆☆☆ Found in Text Mining only
Osteoarthritis, Knee	Knee osteoarthritis	BEFREE	22440827		★☆☆☆☆ Found in Text Mining only
ovarian neoplasm	Ovarian neoplasm	BEFREE	12805404, 21805246		★☆☆☆☆ Found in Text Mining only
ovarian neoplasm	Ovarian neoplasm	LHGDN	12805404		★☆☆☆☆ Found in Text Mining only
Pancreatic carcinoma	Pancreatic carcinoma	BEFREE	27779720		★☆☆☆☆ Found in Text Mining only
Prostate carcinoma	Prostate cancer	BEFREE	23226097, 24318887, 24913567, 26114115, 26604689, 27779720, 28287731, 28347547, 28456517, 28483279, 28722823, 28993410, 30180568, 30501188, 30765725		★☆☆☆☆ Found in Text Mining only
Prostatic Neoplasms	Prostatic neoplasm	Pubtator	23126600, 26604689, 30340539, 35410344	Associate	★☆☆☆☆ Found in Text Mining only
Refractory anemias	Anemia	BEFREE	28944919		★☆☆☆☆ Found in Text Mining only
Rheumatoid Arthritis	Rheumatoid arthritis	BEFREE	25433529, 26119758, 28944919		★☆☆☆☆ Found in Text Mining only
Skin Neoplasms	Skin Neoplasms	BEFREE	20651981		★☆☆☆☆ Found in Text Mining only
Small Cell Lung Carcinoma	Small cell lung carcinoma	Pubtator	9166946	Associate	★☆☆☆☆ Found in Text Mining only
Squamous cell carcinoma	Carcinoma	BEFREE	23441131		★☆☆☆☆ Found in Text Mining only
Squamous cell carcinoma of skin	Skin carcinoma	BEFREE	20651981		★☆☆☆☆ Found in Text Mining only
Stomach Neoplasms	Stomach neoplasms	Pubtator	39206893	Associate	★☆☆☆☆ Found in Text Mining only
Thyroid Neoplasms	Thyroid cancer	Pubtator	30340539	Associate	★☆☆☆☆ Found in Text Mining only