PCSK1N

Summary

PCSK1N (proprotein convertase subtilisin/kexin type 1 inhibitor, HGNC:17301) is a protein-coding gene on chromosome Xp11.23, encoding ProSAAS (Q9UHG2). May function in the control of the neuroendocrine secretory pathway.

The protein encoded by this gene functions as an inhibitor of prohormone convertase 1, which regulates the proteolytic cleavage of neuroendocrine peptide precursors. The proprotein is further processed into multiple short peptides. A polymorphism within this gene may be associated with obesity.

Source: NCBI Gene 27344 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 49 total
• MANE Select transcript: NM_013271

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17301
Approved symbol	PCSK1N
Name	proprotein convertase subtilisin/kexin type 1 inhibitor
Location	Xp11.23
Locus type	gene with protein product
Status	Approved
Aliases	SAAS, SgVIII, SCG8, proSAAS, PEN, BigLEN
Ensembl gene	ENSG00000102109
Ensembl biotype	protein_coding
OMIM	300399
Entrez	27344

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000218230, ENST00000611033, ENST00000884092, ENST00000967544, ENST00000967545

RefSeq mRNA: 1 — MANE Select: NM_013271 NM_013271

CCDS: CCDS14307

Canonical transcript exons

ENST00000218230 — 3 exons

Exon	Start	End
ENSE00000670885	48831869	48832341
ENSE00001885508	48835419	48835610
ENSE00001958719	48831096	48831455

Expression profiles

Bgee: expression breadth ubiquitous, 210 present calls, max score 99.75.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 51.4689 / max 2210.6748, expressed in 1049 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
199188	51.4689	1049

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adenohypophysis	UBERON:0002196	99.75	gold quality
pituitary gland	UBERON:0000007	99.69	gold quality
type B pancreatic cell	CL:0000169	99.45	gold quality
nucleus accumbens	UBERON:0001882	99.24	gold quality
anterior cingulate cortex	UBERON:0009835	99.09	gold quality
cingulate cortex	UBERON:0003027	99.07	gold quality
amygdala	UBERON:0001876	99.06	gold quality
right frontal lobe	UBERON:0002810	99.02	gold quality
caudate nucleus	UBERON:0001873	98.95	gold quality
hypothalamus	UBERON:0001898	98.74	gold quality
putamen	UBERON:0001874	98.45	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	98.43	gold quality
Brodmann (1909) area 9	UBERON:0013540	98.40	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	98.15	gold quality
right hemisphere of cerebellum	UBERON:0014890	98.05	gold quality
temporal lobe	UBERON:0001871	97.65	gold quality
spinal cord	UBERON:0002240	97.63	gold quality
frontal cortex	UBERON:0001870	97.52	gold quality
forebrain	UBERON:0001890	97.52	gold quality
telencephalon	UBERON:0001893	97.32	gold quality
postcentral gyrus	UBERON:0002581	97.29	gold quality
neocortex	UBERON:0001950	97.26	gold quality
cerebellar cortex	UBERON:0002129	97.26	gold quality
prefrontal cortex	UBERON:0000451	97.24	gold quality
cerebellar hemisphere	UBERON:0002245	97.22	gold quality
parietal lobe	UBERON:0001872	97.19	gold quality
cortical plate	UBERON:0005343	97.12	gold quality
cerebral cortex	UBERON:0000956	97.10	gold quality
brain	UBERON:0000955	97.09	gold quality
Ammon’s horn	UBERON:0001954	97.00	gold quality

Single-cell (SCXA)

Detected in 27 experiment(s), a significant marker in 24.

Experiment	Marker?	Max mean expression
E-MTAB-9906	yes	7951.83
E-GEOD-125970	yes	7117.01
E-MTAB-5061	yes	5337.73
E-MTAB-8410	yes	3570.24
E-MTAB-8221	yes	3524.62
E-HCAD-31	yes	3340.46
E-HCAD-15	yes	2620.41
E-CURD-114	yes	2463.50
E-HCAD-56	yes	2286.31
E-MTAB-9435	yes	2098.56
E-MTAB-8894	yes	2011.31
E-MTAB-11121	yes	1573.36
E-MTAB-10662	yes	771.15
E-GEOD-93593	yes	483.47
E-MTAB-9543	yes	329.18

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F4, ISL1, PAX6

miRNA regulators (miRDB)

12 targeting PCSK1N, 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-6759-5P	99.99	66.54	785
HSA-MIR-5100	99.11	67.52	1098
HSA-MIR-1288-5P	98.85	67.01	734
HSA-MIR-6787-5P	97.54	63.85	457
HSA-MIR-96-3P	97.47	68.03	839
HSA-MIR-6762-5P	96.55	64.62	972
HSA-MIR-6845-5P	96.55	64.65	969
HSA-MIR-4296	96.35	63.55	1233
HSA-MIR-6796-5P	95.37	66.08	1120
HSA-MIR-663A	94.99	63.54	378
HSA-MIR-10396B-5P	94.99	63.57	358
HSA-MIR-1908-5P	94.99	63.41	352

Literature-anchored findings (GeneRIF, showing 5)

• although both proSAAS and 7B2 potently inhibit PC enzymes via a C-terminal peptide, their intracellular interactions with PCs appear to differ significantly, with each binding protein exhibiting unique properties (PMID:11719503)
• ProSAAS or proSAAS-like molecules are trapped within tau fibrils and accumulate in tau inclusions in patients with Alzheimer’s disease and parkinsonism-dementia complex. (PMID:14746899)
• Cloning of proSAAS homologs in Danio and Xenopus identifies conserved, putatively functional areas. (PMID:18948394)
• Results show significant differences in distribution of single nucleotide polymorphism in this gene amongst whites and hispanics (PMID:22695173)
• neuronal proSAAS plays an important role in proteostatic processes. (PMID:27457957)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Pcsk1n	ENSMUSG00000039278
rattus_norvegicus	Pcsk1n	ENSRNOG00000046021

Protein

Protein identifiers

ProSAAS — Q9UHG2 (reviewed: Q9UHG2)

Alternative names: Proprotein convertase subtilisin/kexin type 1 inhibitor, pro-SAAS

All UniProt accessions (1): Q9UHG2

UniProt curated annotations — full annotation on UniProt →

Function. May function in the control of the neuroendocrine secretory pathway. Proposed be a specific endogenous inhibitor of PCSK1. ProSAAS and Big PEN-LEN, both containing the C-terminal inhibitory domain, but not the further processed peptides reduce PCSK1 activity in the endoplasmic reticulum and Golgi. It reduces the activity of the 84 kDa form but not the autocatalytically derived 66 kDa form of PCSK1. Subsequent processing of proSAAS may eliminate the inhibition. Slows down convertase-mediated processing of proopiomelanocortin and proenkephalin. May control the intracellular timing of PCSK1 rather than its total level of activity. Endogenous ligand for GPR171. Neuropeptide involved in the regulation of feeding. Endogenous ligand for GPR83. Neuropeptide involved in the regulation of feeding.

Subunit / interactions. Interacts via the C-terminal inhibitory domain with PCSK1 66 kDa form.

Subcellular location. Secreted. Golgi apparatus. trans-Golgi network.

Tissue specificity. Expressed in brain and pancreas.

Post-translational modifications. Proteolytically cleaved in the Golgi. O-glycosylated with a core 1 or possibly core 8 glycan.

Domain organisation. ProSAAS(1-180) increases secretion of enzymatically inactive PCSK1. The C-terminal inhibitory domain is involved in inhibition of PCSK1. It corresponds to the probable processing intermediate Big PEN-LEN, binds to PCSK1 in vitro and contains the hexapeptide L-L-R-V-K-R, which, as a synthetic peptide, is sufficient for PCSK1 inhibition. The four C-terminal amino acids of Big LEN are sufficient to bind and activate GPR171.

RefSeq proteins (1): NP_037403* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR010832	ProSAAS	Family

Pfam: PF07259

UniProt features (28 total): mutagenesis site 10, peptide 7, region of interest 3, glycosylation site 3, signal peptide 1, chain 1, short sequence motif 1, compositionally biased region 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UHG2-F1	59.56	0.04

Functional residue map

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

Glycosylation sites (3): 53, 228, 247

Mutagenesis-validated functional residues (10):

Position	Phenotype
235	reduces inhibition of pcsk1.
236	greatly reduces inhibition of pcsk1.
237	reduces inhibition of pcsk1.
240	reduces inhibition of pcsk1.
241	reduces inhibition of pcsk1.
242	reduces inhibition of pcsk1.
243	abolishes inhibition of pcsk1.
244	abolishes inhibition of pcsk1.
245	reduces inhibition of pcsk1.
246	reduces inhibition of pcsk1.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 140 (showing top): GOBP_BEHAVIOR, TGCGCANK_UNKNOWN, GOBP_RESPONSE_TO_COLD, GOCC_SECRETORY_GRANULE, GOBP_RESPONSE_TO_DIETARY_EXCESS, GCANCTGNY_MYOD_Q6, GOBP_REGULATION_OF_HORMONE_LEVELS, GGGTGGRR_PAX4_03, HANN_RESISTANCE_TO_BCL2_INHIBITOR_UP, GOBP_REGULATION_OF_BEHAVIOR, GOBP_REGULATION_OF_FEEDING_BEHAVIOR, GOBP_PROTEIN_MATURATION, GOCC_TRANS_GOLGI_NETWORK, GOBP_AMIDE_METABOLIC_PROCESS, WCTCNATGGY_UNKNOWN

GO Biological Process (5): response to dietary excess (GO:0002021), neuropeptide signaling pathway (GO:0007218), response to cold (GO:0009409), peptide hormone processing (GO:0016486), negative regulation of endopeptidase activity (GO:0010951)

GO Molecular Function (3): endopeptidase inhibitor activity (GO:0004866), serine-type endopeptidase inhibitor activity (GO:0004867), signaling receptor binding (GO:0005102)

GO Cellular Component (5): obsolete extracellular space (GO:0005615), trans-Golgi network (GO:0005802), secretory granule (GO:0030141), extracellular region (GO:0005576), Golgi apparatus (GO:0005794)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
endopeptidase activity	2
endomembrane system	2
response to nutrient levels	1
energy homeostasis	1
G protein-coupled receptor signaling pathway	1
response to stress	1
response to temperature stimulus	1
hormone metabolic process	1
signaling receptor ligand precursor processing	1
negative regulation of peptidase activity	1
regulation of endopeptidase activity	1
peptidase inhibitor activity	1
endopeptidase regulator activity	1
serine-type endopeptidase activity	1
endopeptidase inhibitor activity	1
protein binding	1
Golgi apparatus subcompartment	1
secretory vesicle	1
cellular anatomical structure	1
cytoplasm	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

738 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PCSK1N	CPE	P16870	886
PCSK1N	GPR171	O14626	862
PCSK1N	PCSK1	P29120	833
PCSK1N	POMC	P01189	723
PCSK1N	GPR83	Q9NYM4	694
PCSK1N	SCG2	P13521	681
PCSK1N	CHGB	P05060	670
PCSK1N	SCG5	P01164	655
PCSK1N	SCG3	Q8WXD2	635
PCSK1N	VGF	O15240	596
PCSK1N	PENK	P01210	583
PCSK1N	PCSK2	P16519	512
PCSK1N	CHGA	P10645	500
PCSK1N	VIPR1	P32241	483
PCSK1N	QRFP	P83859	483

IntAct

18 interactions, top by confidence:

A	B	Type	Score
MGAT4C	GXYLT2	psi-mi:“MI:0914”(association)	0.530
MMP10	TIMP1	psi-mi:“MI:0914”(association)	0.530
ADAM21	PLXNA2	psi-mi:“MI:0914”(association)	0.530
ADCYAP1	GGPS1	psi-mi:“MI:0914”(association)	0.530
PLA2G3	PCSK1N	psi-mi:“MI:0915”(physical association)	0.400
PCSK1N	RAD51	psi-mi:“MI:0915”(physical association)	0.370
APP	ESYT2	psi-mi:“MI:0914”(association)	0.350
DKKL1	VWA8	psi-mi:“MI:0914”(association)	0.350
ADAM21	PLXNB2	psi-mi:“MI:0914”(association)	0.350
ADCYAP1	CETN3	psi-mi:“MI:0914”(association)	0.350
DYRK1A	TEX13D	psi-mi:“MI:0914”(association)	0.350
ST3GAL4	NDUFA4	psi-mi:“MI:0914”(association)	0.350
PCSK1N	CLTCL1	psi-mi:“MI:0914”(association)	0.350
CHST13	NUCB1	psi-mi:“MI:0914”(association)	0.350
SLC10A5	STXBP3	psi-mi:“MI:0914”(association)	0.350

BioGRID (23): PCSK1N (Affinity Capture-MS), PCSK1N (Affinity Capture-MS), PCSK1N (Two-hybrid), PCSK1N (Affinity Capture-MS), PCSK1N (Affinity Capture-MS), PCSK1N (Affinity Capture-MS), PCSK1N (Affinity Capture-MS), PCSK1N (Affinity Capture-MS), CLTCL1 (Affinity Capture-MS), PCSK1N (Affinity Capture-MS), PCSK1N (Affinity Capture-MS), MTX3 (Affinity Capture-MS), AGO4 (Affinity Capture-MS), PCSK1N (Affinity Capture-MS), PDSS2 (Affinity Capture-MS)

ESM2 similar proteins: A2VD12, A6QLY7, A8MVW0, E7EW31, I3L3R5, O15240, O35314, P01142, P04404, P05059, P05060, P10354, P10645, P13207, P16014, P20156, P23389, P23943, P26339, P33671, P48299, P86435, Q0VGU4, Q1HCM0, Q1RMJ9, Q3KP66, Q3MI48, Q3TVI8, Q60478, Q6R6L0, Q765Z4, Q765Z5, Q7TN12, Q80VC9, Q867D0, Q8K262, Q8MJW9, Q8TAT2, Q924A2, Q95MI6

Diamond homologs: Q9QXU9, Q9QXV0, Q9UHG2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	45
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

604 predictions. Top by Δscore:

Variant	Effect	Δscore
X:48832339:CTC:C	acceptor_gain	1.0000
X:48832340:TC:T	acceptor_gain	1.0000
X:48832341:CC:C	acceptor_gain	1.0000
X:48832341:CCTGC:C	acceptor_loss	1.0000
X:48832342:CTG:C	acceptor_loss	1.0000
X:48832352:A:C	acceptor_gain	1.0000
X:48831873:A:C	donor_gain	0.9900
X:48832337:GGCTC:G	acceptor_gain	0.9900
X:48832338:GCTC:G	acceptor_gain	0.9900
X:48832339:CTCC:C	acceptor_gain	0.9900
X:48832340:TCCT:T	acceptor_gain	0.9900
X:48832342:C:CC	acceptor_gain	0.9900
X:48832346:G:T	acceptor_gain	0.9900
X:48832352:A:AC	acceptor_gain	0.9900
X:48835415:GCACC:G	donor_loss	0.9900
X:48835416:CACC:C	donor_loss	0.9900
X:48835417:A:T	donor_loss	0.9900
X:48835418:C:CG	donor_loss	0.9900
X:48831911:T:TA	donor_gain	0.9800
X:48832357:G:C	acceptor_gain	0.9800
X:48831908:G:A	donor_gain	0.9700
X:48832357:G:GC	acceptor_gain	0.9700
X:48834589:T:TA	donor_gain	0.9700
X:48834651:C:CT	acceptor_gain	0.9700
X:48834651:C:T	acceptor_gain	0.9600
X:48835130:AGTG:A	donor_gain	0.9600
X:48831870:TCA:T	donor_gain	0.9500
X:48831890:T:TA	donor_gain	0.9500
X:48832342:C:T	acceptor_gain	0.9500
X:48832345:C:CT	acceptor_gain	0.9500

AlphaMissense

1591 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:48831314:T:A	K243N	0.996
X:48831314:T:G	K243N	0.996
X:48831315:T:A	K243I	0.996
X:48832211:A:G	L82P	0.992
X:48831869:C:A	R196M	0.991
X:48831438:A:G	I202T	0.990
X:48832203:C:G	A85P	0.990
X:48831450:A:G	L198S	0.989
X:48831872:A:G	L195S	0.989
X:48832220:A:G	L79P	0.986
X:48832046:G:T	A137D	0.985
X:48832037:A:G	L140P	0.983
X:48832119:A:G	W113R	0.983
X:48832119:A:T	W113R	0.983
X:48831875:A:G	L194P	0.982
X:48832117:C:A	W113C	0.981
X:48832117:C:G	W113C	0.981
X:48831315:T:G	K243T	0.980
X:48831316:T:C	K243E	0.980
X:48831438:A:C	I202S	0.979
X:48832196:C:G	R87P	0.978
X:48832130:A:G	L109P	0.976
X:48832173:C:G	A95P	0.976
X:48831438:A:T	I202N	0.975
X:48831884:T:A	D191V	0.975
X:48831447:A:G	L199P	0.973
X:48831884:T:C	D191G	0.973
X:48831445:C:G	G200R	0.972
X:48831445:C:T	G200R	0.972
X:48832037:A:T	L140Q	0.972

dbSNP variants (sampled 300 via entrez): RS1001983888 (X:48831774 G>A), RS1002013414 (X:48832289 G>A,T), RS1002985240 (X:48834382 C>A,T), RS1003016620 (X:48834844 G>C), RS1004393717 (X:48837166 C>T), RS1006489023 (X:48834158 T>C), RS1007126447 (X:48833618 A>G), RS1008127640 (X:48836621 T>C), RS1010691892 (X:48832949 C>T), RS1011666589 (X:48834996 G>A), RS1011699191 (X:48835729 C>T), RS1012670875 (X:48837560 G>A), RS1018128770 (X:48836633 T>G), RS1020103734 (X:48830629 A>G), RS1020688402 (X:48832987 T>C)

Disease associations

OMIM: gene MIM:300399 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST007847_105	Type 2 diabetes	5.000000e-09

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, increases methylation, affects expression	4
Cyclosporine	decreases expression, increases expression	3
Particulate Matter	decreases expression, increases abundance	2
6,7-dimethoxy-2-(pyrrolidin-1-yl)-N-(5-(pyrrolidin-1-yl)pentyl)quinazolin-4-amine	decreases expression	1
bisphenol A	affects expression	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
CGP 52608	affects binding, increases reaction	1
corosolic acid	increases expression	1
jinfukang	affects cotreatment, increases expression	1
MT19c compound	decreases expression	1
Resveratrol	decreases expression, affects cotreatment	1
Air Pollutants	decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Cadmium	increases expression	1
Cisplatin	affects cotreatment, increases expression	1
Cocaine	decreases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Diethylhexyl Phthalate	decreases expression	1
Lead	affects expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Triclosan	increases expression	1
Cadmium Chloride	increases expression	1

Clinical trials (associated diseases)

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