Affinage

PCSK1

Neuroendocrine convertase 1 · UniProt P29120

Length
753 aa
Mass
84.2 kDa
Annotated
2026-06-10
100 papers in source corpus 36 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PCSK1 encodes PC1/3, a calcium-dependent serine endoprotease of the subtilisin/kexin class that is the principal neuroendocrine convertase of the regulated secretory pathway, cleaving prohormones at paired basic residues with a preference for arginine at the P4 position (PMID:2023902, PMID:8449925, PMID:7713926). Its activity is built through ordered maturation: autocatalytic removal of the prosegment at the RSKR80–83 motif occurs early in the ER, while major substrate processing and a subsequent C-terminal truncation at Arg590-Arg591 that activates the enzyme occur later in dense core secretory granules (PMID:8449925, PMID:7559585); N-glycosylation and an intact RRGDL P-domain motif are required for folding, zymogen processing, and granule sorting, with misfolding-prone mutants routed to ER-associated degradation (PMID:8397508, PMID:9307023, PMID:26207343). Sorting to dense core secretory granules is mediated by a C-terminal amphipathic helix (residues 738–750) anchored by Leu745, whose calcium-promoted aggregation links calcium sensing to granule targeting (PMID:19376969). Within granules, processing requires the regulated secretory environment rather than propeptide removal alone (PMID:1597471), and PC1/3 activity is restrained by endogenous inhibitors—its own propeptide and the proSAAS-derived SAAS CT peptide—and modulated by oligomerization and substrate-induced activation (PMID:9813073, PMID:10812060, PMID:21303942). PC1/3 cleaves a defined set of substrates including POMC→ACTH/β-LPH, proinsulin, proGHRH, proglucagon→GLP-1/GLP-2, proenkephalin, prosomatostatin, proneurotensin, VGF, and pro-CART (PMID:2023902, PMID:8449925, PMID:8095501, PMID:7559585, PMID:12145326, PMID:12065665, PMID:12584191), and loss of PC1/3 in mice and humans causes obesity, hyperproinsulinemia, dwarfism, and multiple endocrinopathies (PMID:12145326, PMID:16644867, PMID:24890885); reduced expression underlies prohormone-processing deficits in Prader-Willi syndrome through a SNORD116→NHLH2→PCSK1 axis (PMID:27941249). Its transcription is controlled by PAX6, Creb3l1, gp130 cytokines (LIF/IL-6), thyroid hormone (negative, via TR-alpha1), and bile acid/TGR5/NFAT signaling (PMID:19034419, PMID:32319174, PMID:10630414, PMID:11120670, PMID:26789236). Beyond its endocrine role, PC1/3 restrains innate immune activation, with its loss driving macrophages toward an M1 phenotype and cytokine storm (PMID:22396549, PMID:26330543).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1991 High

    Establishing that PC1/3 has a distinct, limited prohormone cleavage specificity answered whether convertases divide labor on a shared substrate, distinguishing it from the broader-acting PC2.

    Evidence Vaccinia co-expression of PC1/PC2 with POMC in multiple cell lines with pulse-chase monitoring

    PMID:2023902

    Open questions at the time
    • Did not define the structural basis of cleavage-site selectivity
    • Specificity tested only on POMC
  2. 1992 High

    Showing PC1/3 processes substrates only in granule-containing cells established that its activity depends on the regulated secretory pathway environment, not merely propeptide removal.

    Evidence Vaccinia expression with biosynthetic labeling comparing granule-containing vs granule-lacking cells using prorenin

    PMID:1597471

    Open questions at the time
    • Molecular features of the granule environment required were not defined
    • Did not identify cofactors supplied by granules
  3. 1993 High

    Biochemical purification and biosynthetic mapping defined PC1/3 as a calcium-dependent acidic-pH serine protease with P4 arginine preference that undergoes early autocatalytic prosegment removal at RSKR80–83, and localized it to the TGN/granule pathway.

    Evidence Recombinant purification, fluorogenic substrate kinetics, pulse-chase, tunicamycin/BFA treatments, immunocytochemistry across cell lines

    PMID:8095501 PMID:8115023 PMID:8380577 PMID:8397508 PMID:8449925

    Open questions at the time
    • C-terminal processing event not yet mechanistically defined
    • Full in vivo substrate repertoire unknown
  4. 1995 High

    Identifying C-terminal truncation at Arg590-Arg591 as an activating, granule-routing event answered how PC1/3 reaches maximal activity after ER prosegment removal.

    Evidence Site-directed mutagenesis of C-terminal paired basic sites with proneurotensin processing in PC12 cells; purification from chromaffin granules with kinetics

    PMID:7559585 PMID:7713926

    Open questions at the time
    • Identity of the protease performing C-terminal cleavage in granules not resolved
    • Quantitative contribution of truncation vs oligomerization to activation unclear
  5. 1997 High

    Defining the RRGDL P-domain motif as essential for zymogen processing, C-terminal autoprocessing, and granule sorting linked a single structural element to the full maturation program.

    Evidence Site-directed mutagenesis, vaccinia expression, pulse-chase, alpha1-PDX inhibition, immunocytochemistry

    PMID:9307023

    Open questions at the time
    • Atomic-level mechanism of how RRGDL coordinates folding and sorting not resolved
  6. 2000 High

    Characterizing the PC1/3 propeptide and the proSAAS-derived SAAS CT peptide as nanomolar inhibitors answered how the enzyme is held latent and activated in a controlled manner.

    Evidence Recombinant propeptide and proSAAS peptide inhibition kinetics, progress-curve analysis, proteolytic mapping

    PMID:10812060 PMID:9813073

    Open questions at the time
    • In vivo stoichiometry of inhibitor-to-enzyme not established
    • Timing of inhibitor inactivation within granules not directly observed
  7. 2002 High

    Knockout of PC1/3 in mice answered which prohormones depend on it in vivo, establishing it as the key convertase for GHRH, POMC, proinsulin, and proglucagon and explaining the growth/endocrine phenotypes.

    Evidence Targeted gene disruption with hormone measurements and tissue-specific processing analysis; complementary VGF cleavage-site mapping

    PMID:12065665 PMID:12145326

    Open questions at the time
    • Did not separate developmental from acute requirements
    • Tissue-specific contributions of redundant convertases not fully dissected
  8. 2003 High

    Comparing PC1/3 and PC2 on pro-CART refined the division of labor between convertases on a shared substrate, assigning intermediate-fragment generation to PC1/3.

    Evidence Transfection in neuroendocrine lines with microsequencing and knockout mouse hypothalamic extract validation

    PMID:12584191

    Open questions at the time
    • Physiological role of PC1/3-generated CART intermediates not defined
  9. 2008 Medium

    Functional characterization of the N221D/N222D variants linked partial PC1/3 activity loss to obesity, establishing that hypomorphic alleles are pathogenic.

    Evidence In vitro enzymatic activity assays of variant PC1/3; mouse N222D mutant metabolic phenotyping

    PMID:16644867 PMID:18604207

    Open questions at the time
    • Quantitative threshold of activity loss causing obesity not defined
    • Background-dependence of the assayed activity (noted later in #26) complicates interpretation
  10. 2009 High

    NMR structure and sorting assays of the C-terminal domain answered how PC1/3 is targeted to dense core granules, defining a calcium-responsive amphipathic helix anchored by Leu745.

    Evidence NMR structure determination, truncation/granule-sorting assays, calcium binding studies

    PMID:19376969

    Open questions at the time
    • Granule receptor or membrane partner engaging the helix not identified
    • Link between aggregation and physiological sorting efficiency not quantified in vivo
  11. 2011 Medium

    Demonstrating oligomerization and substrate-induced activation provided a model for how PC1/3 activity is tuned by its own substrates within granules.

    Evidence Ion exchange, gel filtration, cross-linking, and fluorogenic activity assays with peptide preincubation

    PMID:21303942

    Open questions at the time
    • Single-lab biochemical model not validated in intact granules
    • Physiological relevance of homodimer latency unconfirmed in vivo
  12. 2012 High

    Discovering immune phenotypes in PC1/3 knockout mice extended its function beyond endocrine prohormone processing to restraint of innate immune cytokine secretion.

    Evidence Knockout mouse LPS challenge, cytokine ELISA, macrophage isolation, electron microscopy; later proteomic M1-polarization analysis

    PMID:22396549 PMID:26330543

    Open questions at the time
    • Macrophage substrate(s) processed by PC1/3 not identified
    • Mechanism linking PC1/3 to TLR4/MyD88 signaling not resolved
  13. 2012 High

    Mapping PAX6→Pcsk1n→PC1/3 and direct PAX6 activation of PCSK1 answered how transcriptional control couples beta-cell identity to prohormone-processing capacity.

    Evidence ChIP, EMSA, luciferase reporters, RNAi rescue, and proinsulin processing assays in mouse and human models

    PMID:19034419 PMID:23056534

    Open questions at the time
    • Quantitative contribution of each arm (direct activation vs proSAAS repression) to net activity not partitioned
  14. 2016 High

    Defining ER-retention dominant-negative mutants and a splice variant established how diverse PCSK1 mutations converge on ER quality control and proteasomal degradation to reduce wild-type activity.

    Evidence Mutagenesis, co-expression of WT+mutant, ER stress markers, pulse-chase, and exon-skipping/trafficking analysis

    PMID:24890885 PMID:26207343 PMID:28271036

    Open questions at the time
    • In vivo contribution of dominant-negative trans-inhibition to human disease severity not quantified
  15. 2017 High

    Human stem-cell and Prader-Willi models answered whether PC1/3 deficiency phenocopies in human neurons and connected PCSK1 to a disease gene network via SNORD116→NHLH2→PCSK1.

    Evidence CRISPR/shRNA disruption in hESC-derived hypothalamic neurons; iPSC PWS neurons and Snord116 KO mice with in vivo prohormone processing

    PMID:27941249 PMID:28132887

    Open questions at the time
    • Therapeutic correction of PC1/3 deficiency in PWS not demonstrated
    • Relative contribution to PWS phenotype vs other affected genes unclear
  16. 2020 High

    Identifying Creb3l1, gp130 cytokines, thyroid hormone, and bile acid/TGR5/NFAT inputs answered how PC1/3 expression is matched to physiological state across cell types.

    Evidence ChIP/EMSA/reporter and in vivo viral manipulation (Creb3l1); promoter-reporter and in vivo (LIF/IL-6, T3); TGR5 agonist with NFAT inhibition; GLP-1R-dependent alpha-cell scRNA-seq

    PMID:10630414 PMID:11120670 PMID:26789236 PMID:32319174 PMID:33554958

    Open questions at the time
    • Integration of competing transcriptional inputs in single cells not modeled
    • Whether expression changes translate to proportional active-enzyme changes not always measured

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular substrate(s) and signaling mechanism by which PC1/3 restrains macrophage M1 activation and innate cytokine release remain undefined.
  • No immune substrate identified
  • Connection between PC1/3 catalytic activity and TLR4/MyD88/calcium signaling not mechanistically established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0016787 hydrolase activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0031410 cytoplasmic vesicle 4 GO:0005783 endoplasmic reticulum 3 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-392499 Metabolism of proteins 4 R-HSA-168256 Immune System 2 R-HSA-9609507 Protein localization 2
Partners
PCSK1NPCSK2

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1991 PC1 (PCSK1) cleaves proopiomelanocortin (POMC) preferentially at two pairs of basic residues to produce corticotropin (ACTH) and beta-lipotropin, demonstrating distinct cleavage specificity compared to PC2 (which has broader activity). This was established by co-expressing PC1 and PC2 with POMC in multiple cell lines including BSC-40, PC12, and AtT-20. Recombinant vaccinia virus co-expression of PC1/PC2 with POMC in multiple cell lines; pulse-chase biosynthetic monitoring Proceedings of the National Academy of Sciences of the United States of America High 2023902
1992 PC1 can process human prorenin to active renin specifically in cells containing secretory granules (e.g., GH4 somatomammotroph cells) but not in cells lacking granules (CHO or BSC-40 cells), demonstrating that PC1 activity on substrates requires the regulated secretory pathway environment, not merely propeptide removal. Vaccinia virus expression system; biosynthetic labeling; comparison of processing in granule-containing vs granule-lacking cell lines The Journal of biological chemistry High 1597471
1993 PC1 and PC2 undergo distinct biosynthetic processing: pro-PC1 (88 kDa) is cleaved to PC1 (83 kDa) in a pre-Golgi compartment (endoplasmic reticulum), with prosegment cleavage occurring early. PC1 is secreted as a glycosylated, sulphated 84 kDa form ~30 min after biosynthesis. N-glycosylation is essential for proper folding and stability of PC1; inhibition with tunicamycin causes ER degradation. Furin cannot cleave pro-PC1. Pulse-chase analysis; low temperature/brefeldin A/CCCP treatment; tunicamycin inhibition; furin co-expression; vaccinia virus expression in GH4C1 cells The Biochemical journal High 8397508
1993 PC1 performs a limited set of POMC cleavages in AtT-20 corticotropes (anterior pituitary pattern: ACTH + beta-LPH), while co-expression of PC2 in these cells enables the full intermediate pituitary cleavage pattern (alpha-MSH, beta-endorphin). PC1-dependent cleavages occur in the earliest biosynthetic steps; PC2-dependent cleavages occur in middle/late steps. Stable transfection of PC2 cDNA into AtT-20 cells; kinetic analysis of biosynthetic processing products The Journal of biological chemistry High 8380577
1993 Purified recombinant mouse PC1 is an 87-kDa calcium-dependent serine proteinase with optimal pH 5.5–6.5, preferring substrates with arginine 4 residues N-terminal to the cleavage site. PC1 undergoes autocatalytic prosegment cleavage at the RSKR motif (residues 80–83) early in biosynthesis. PC1 cleaves proenkephalin to yield a peptide B-sized fragment, demonstrating a role in proenkephalin processing. Purification from CHO cell conditioned medium; fluorogenic substrate specificity studies; pulse-chase biosynthesis; in vitro cleavage of proenkephalin The Journal of biological chemistry High 8449925
1993 PC1 is concentrated in a trans-Golgi network (TGN)-like compartment in AtT-20 cells and is co-transported with processed peptide (met-enkephalin) to the tips of cell processes (secretory granules). Brefeldin A treatment disrupts PC1 localization to the TGN region, confirming Golgi-dependent localization. Immunocytochemistry; dual-staining with TGN38 marker; brefeldin A treatment; subcellular fractionation Neuroendocrinology Medium 8115023
1993 PC1 (but not PC2) can cleave prosomatostatin at the dibasic Arg-Lys site to produce somatostatin-14 when co-expressed in COS-7 cells, demonstrating that PC1 mediates dibasic cleavage of prosomatostatin in the regulated secretory pathway. Co-expression of PC1/PC2 with prosomatostatin in COS-7, AtT-20, and PC12 cells; comparison of processing products by RIA and HPLC The Journal of biological chemistry Medium 8095501
1995 PC1/3 and PC2 are purified from bovine adrenal medulla chromaffin granules as 66-kDa Ca2+-dependent serine proteases. PC1/3 shows pH optimum of 6.5, cleaves paired basic and monobasic sites in peptide substrates (Km ~66 µM for Boc-Arg-Val-Arg-Arg-MCA), and is inhibited by EGTA, thiol-blocking reagents, and active-site-directed chloromethyl ketone inhibitors. Purification from chromaffin granules by chromatography; kinetic studies with fluorogenic peptide substrates; inhibitor profiling; immunoaffinity purification The Journal of biological chemistry High 7713926
1995 The 66-kDa C-terminally truncated form of PC1, generated by cleavage at Arg590-Arg591 in the C-terminal tail, is efficiently routed to secretory granules and retains full processing activity on proneurotensin. C-terminal truncation of PC1 regulates its activity—blocking this cleavage site reduces processing efficiency, suggesting C-terminal processing serves to activate the enzyme. Site-directed mutagenesis of paired basic sites in C-terminal tail; PC12 cell expression; proneurotensin processing assay The Journal of biological chemistry High 7559585
1997 The RRGDL motif in the P-domain of PC1 is critical for zymogen processing in the ER, C-terminal auto-processing to the 66-kDa form in secretory granules, and proper sorting to the regulated secretory pathway. Mutations in this motif cause increased ER degradation, prevent granule sorting, and route PC1 to the constitutive pathway, reducing POMC processing activity. Site-directed mutagenesis of RRGDL motif; vaccinia virus expression; pulse-chase analysis; alpha1-PDX inhibitor; immunocytochemistry The Biochemical journal High 9307023
1998 The propeptide of PC1/3 (residues 1–98) functions as a potent slow tight-binding inhibitor of active PC1/3 (Ki in low nanomolar range) and also weakly inhibits PC2 (micromolar Ki, competitive). Cleavage within residues 1–71 abrogates inhibitory potency. The propeptide is itself cleaved by mature PC1/3. Recombinant propeptide isolation from baculovirus-infected insect cells; progress curve kinetic analysis; inhibition assays with murine 71-kDa PC1/3 and human furin The Journal of biological chemistry High 9813073
1999 PC1 propeptide cleavage occurs rapidly in the ER, yet PC1's major substrate processing occurs later (secretory granules). PC1 undergoes a C-terminal processing event that activates the enzyme. ProPC2 requires the chaperone 7B2 for generation of catalytically active PC2, but this is not required for PC1 activation. Biochemical fractionation; pulse-chase analysis; review integrating multiple experimental systems Progress in nucleic acid research and molecular biology Medium 10506829
2000 The granin-related protein proSAAS contains a C-terminal hexapeptide (SAAS CT peptide) that is a potent nanomolar inhibitor of PC1, functioning as a tight-binding competitive inhibitor. Recombinant PC1 can cleave the proSAAS CT peptide following the inhibitory hexapeptide, suggesting autoinactivation of the inhibitor. Recombinant protein inhibition assay; peptide library comparison; proteolytic mapping; structural analogy to 7B2/PC2 system FEBS letters Medium 10812060
2002 PC1/3 knockout mice display severe postnatal growth impairment (~60% of normal size) and multiple prohormone processing defects including: failure to cleave GHRH (leading to low GH and IGF-1), defective POMC→ACTH processing in pituitary, hyperproinsulinemia (impaired proinsulin→insulin conversion), and failure of proglucagon→GLP-1/GLP-2 conversion in intestine. This definitively establishes PC1/3 as a key neuroendocrine convertase for these specific substrates in vivo. Targeted gene disruption (knockout mouse); phenotypic analysis; hormone measurements; mRNA analysis Proceedings of the National Academy of Sciences of the United States of America High 12145326
2002 Both PC1/3 and PC2 can generate VGF20 from the VGF precursor, while VGF10 production is preferentially mediated by PC1/3. PC1/3 cleaves at the RPR555 site to generate VGF10. The KRKRKK488 motif is the target for VGF20 generation. Ectopic expression of PC1/3 and PC2 in GH3 cells; site-directed mutagenesis of VGF cleavage sites; mass spectrometry and Edman degradation of products Journal of neurochemistry Medium 12065665
2003 PC2 is more efficient than PC1/3 in generating bioactive CART I (residues 55–102) from pro-CART, while bioactive CART II (residues 62–102) is exclusively generated by PC2. PC1/3 is predominantly responsible for generating intermediate CART fragments (33–102 and 10–89). These results were confirmed in PC2, 7B2, and PC1/3 knockout mouse hypothalamic extracts. Transient transfection in neuroendocrine cell lines; microsequencing; HPLC/mass spectrometry; knockout mouse hypothalamic extract analysis The Journal of biological chemistry High 12584191
2006 A mouse PC1 N222D missense mutation causes obesity, impairs autocatalytic activation of mature PC1, reduces hypothalamic alpha-MSH (through defective POMC processing), and leads to abnormal proinsulin processing and glucose intolerance. This demonstrates that a partial loss of PC1 activity is sufficient to cause obesity in mice. Mouse mutant allele characterization; enzyme activity assays; hormone measurements; metabolic phenotyping Human molecular genetics High 16644867
2007 Expression of PC1/3 (instead of PC2) in alpha-cells redirects proglucagon processing from glucagon production to GLP-1 and GLP-2 production, improving glucose tolerance and promoting beta-cell proliferation. The glucose-lowering effect was attenuated in GLP-1R-/- mice, confirming that PC1/3-mediated GLP-1 production is the key mechanism. Transplantation of alpha-cells stably expressing PC1/3 vs PC2 in mice; GLP-1R knockout mice; hormone measurements; glucose tolerance tests Diabetes High 17698597
2008 The PCSK1 nonsynonymous variant N221D (rs6232) significantly impairs PC1/3 catalytic activity in functional assays, linking this common variant to obesity risk. Functional enzymatic activity assays of N221D mutant PC1/3 compared to wild-type Nature genetics Medium 18604207
2008 PAX6 transcription factor binds the PC1/3 (PCSK1) promoter and directly upregulates PC1/3 expression. PAX6 deficiency reduces PC1/3 expression, leading to defective proinsulin processing and abnormal glucose metabolism in both mice (Pax6 R266Stop) and humans (PAX6 R240Stop). Promoter binding assays (ChIP, EMSA); mouse and human genetic models; PC1/3 protein and mRNA measurements; proinsulin processing assays Diabetologia High 19034419
2009 The extreme C-terminal sorting domain of PC1/3 (residues 711–753) contains two alpha-helices (722–728 and 738–750). The second helix is necessary and sufficient to target a constitutively secreted protein to dense core secretory granules (DCSGs). Leucine 745 anchors a hydrophobic patch critical for sorting. Calcium binding by this helix promotes aggregation via the hydrophobic patch, linking calcium to DCSG sorting of PC1/3. NMR structure determination; functional granule-sorting assays with truncation mutants; calcium binding studies Proceedings of the National Academy of Sciences of the United States of America High 19376969
2011 PC1/3 exists as multiple ionic forms due to oligomerization and aggregation. The most active form of 87-kDa PC1/3 is a probable homodimer with latent activity revealed by dilution. Preincubation with fluorogenic substrate or peptides containing paired basic residues stabilizes and activates PC1/3, suggesting that substrate binding regulates enzyme activity within secretory granules. Ion exchange chromatography; 2D gel electrophoresis; gel filtration; cross-linking; enzymatic activity assays with fluorogenic substrates Endocrinology Medium 21303942
2012 PC1/3 is expressed in macrophages, and PC1/3 knockout mice have enlarged, disorganized spleens with depletion of dendritic cells. When challenged with LPS, PC1/3 KO mice exhibit cytokine storm with markedly elevated IL-6, IL-1β, and TNF-α plasma levels and are hypersusceptible to septic shock, demonstrating a role for PC1/3 in regulating innate immune cytokine secretion in macrophages. PC1/3 knockout mouse; LPS challenge; cytokine ELISA; immunohistochemistry; peritoneal macrophage isolation; electron microscopy The Journal of biological chemistry High 22396549
2012 Pax6 directly binds the Pcsk1n (proSAAS) promoter and down-regulates its expression. Elevated proSAAS in Pax6-mutant mice inhibits PC1/3 C-terminal cleavage and activity, impairing proinsulin processing. This inhibition can be rescued by proSAAS knockdown, establishing a Pax6→Pcsk1n→PC1/3 regulatory axis in beta cells. Luciferase reporter assay; ChIP; EMSA; RNAi knockdown; enzyme activity assays; proinsulin processing measurements PloS one High 23056534
2014 A heterozygous nonsense mutation PCSK1-p.Arg80* encodes a truncated propeptide that inhibits PC1/3 enzyme activity, likely through a dominant-negative mechanism not requiring strong direct physical interaction. This establishes that truncated PC1/3 propeptide can inhibit wild-type PC1/3 activity in trans. In vitro functional enzyme activity assays; co-expression studies; family segregation analysis International journal of obesity Medium 24890885
2015 PC1/3 inhibition in macrophages (by knockdown or PC1/3 KO) drives macrophages toward an M1 activated phenotype characterized by filopodial extensions, TLR4/MyD88-dependent signaling, increased calcium entry, and secretion of pro-inflammatory factors. This was shown in both NR8383 macrophages and PC1/3 KO mouse macrophages. Proteomics of secretomes and intracellular proteins; PC1/3 knockdown in NR8383 cells; PC1/3 KO mouse macrophages; calcium imaging Molecular & cellular proteomics Medium 26330543
2015 ER-retained PC1/3 mutants (G209R and G593R) induce ER stress and exert dominant-negative effects on wild-type PC1/3, blocking prodomain cleavage and decreasing wild-type PC1/3 expression by routing it to a proteasomal degradation pathway. The N221D variant shows ~30% lower enzymatic activity than wild-type in the correct background (wild-type PC1/3, not S357G hypermorphic background). Site-directed mutagenesis; transfection of WT + mutant constructs; ER stress marker measurement; fluorogenic enzyme activity assays; pulse-chase analysis Endocrinology High 26207343
2016 PC1/3 deficiency in Prader-Willi syndrome (PWS) is due to reduced SNORD116→NHLH2→PCSK1 expression. PC1/3 content and activity were reduced in islets, hypothalamus, and stomach of Snord116 paternal knockout mice, leading to in vivo functional defects in prohormone processing of proinsulin, pro-GHRH, and proghrelin. iPSC-derived neurons from PWS patients; Snord116 knockout mice; PC1/3 protein measurements; in vivo prohormone processing assays The Journal of clinical investigation High 27941249
2016 PC1/3 deficiency in human embryonic stem cell-derived hypothalamic neurons increases unprocessed POMC and decreases ratios of processed POMC-derived peptides (phenocopying PC1/3-null mice), is associated with increased melanocortin receptor expression and increased PRCP (alpha-MSH catabolism), and reduces ACTH secretion. CRISPR-Cas9 and shRNA-mediated PCSK1 disruption in hESC-derived hypothalamic neurons; POMC peptide measurements; receptor expression analysis Stem cell reports High 28132887
2016 A novel PCSK1 variant c.1095+1G>A causes exon 8 skipping, complete loss of PC1/3 enzymatic activity, ER retention of the protein, and ER stress. This mechanistically links splicing mutations to ER quality control in PCSK1 disease. Exon skipping analysis; enzyme activity assay; cell trafficking experiments; ER stress marker measurement Molecular metabolism Medium 28271036
2016 Intestinal bile acids activate TGR5 receptor, which signals through nuclear factor of activated T cells (NFAT) to induce PC1/3 (PCSK1) gene expression in intestinal L-cells, thereby increasing GLP-1 production. This pathway mediates the antidiabetic effect of bile acid binding resins. TGR5-dependent colestimide treatment in mice; NFAT pathway inhibition; PC1/3 gene expression measurement; GLP-1 secretion assays Endocrinology Medium 26789236
2020 Transcription factor Creb3l1 directly binds a G-box motif in the Pcsk1 promoter and upregulates PC1/3 expression in corticotroph and magnocellular neuroendocrine cells. Viral overexpression of Creb3l1 in supraoptic nuclei increases Pcsk1, and knockdown decreases it. No Creb3l1-Pcsk1 relationship was found in the neurointermediate lobe, indicating cell-type specificity. RNA-sequencing; viral overexpression and knockdown in vivo; in vitro promoter luciferase assay; ChIP; EMSA Journal of neuroendocrinology High 32319174
2021 GLP-1 receptor (GLP-1R) agonist liraglutide increases PC1/3 (PCSK1) mRNA expression in a subcluster of pancreatic alpha-cells in a beta-cell GLP-1R-dependent manner. This is associated with increased bihormonal insulin+/glucagon+ cells and expression of other beta-cell-like genes, establishing a GLP-1-mediated paracrine pathway that induces alpha-cell PC1/3 expression. Mouse model with beta cell-specific GLP-1R; scRNA-seq (DART-Seq); IHC; liraglutide treatment JCI insight Medium 33554958
1999 Leukemia inhibitory factor (LIF) and IL-6 (cytokines signaling through gp130/JAK-STAT) upregulate PC1 protein and mRNA in AtT-20 corticotroph cells. This upregulation increases POMC processing to ACTH. LPS administration in vivo also increases pituitary PC1 and POMC mRNA. PC1 promoter activity is directly increased by LIF/IL-6, demonstrating transcriptional regulation by gp130 cytokines. AtT-20 cell treatment with LIF/IL-6; PC1 protein and mRNA measurement; PC1 promoter-luciferase transfection assay; in vivo LPS administration Molecular and cellular endocrinology Medium 10630414
2001 Thyroid hormone (T3) negatively regulates PC1 transcription through multiple thyroid hormone response elements (TREs) located at -10 to +19 bp relative to the transcription start site of the hPC1 promoter. TR-alpha1 binds this region as monomer, homodimer, and heterodimer with RXR-beta. Hypothyroidism increases and hyperthyroidism decreases pituitary PC1 mRNA. Promoter deletion analysis; EMSA with purified TR-alpha1 and RXR-beta; point mutation of TREs; pituitary PC1 mRNA measurement in hypothyroid/hyperthyroid rats American journal of physiology. Endocrinology and metabolism High 11120670
2004 proSAAS expression in AtT-20 cells inhibits both C-terminal processing of PC1 and POMC processing under pulse-chase conditions. The PC1 propeptide expressed in trans also inhibits PC1 C-terminal processing and POMC cleavage, but SAAS CT peptide-propeptide chimeras are less effective in the regulated pathway. AtT-20 cell transfection with proSAAS and propeptide constructs; pulse-chase analysis; POMC and PC1 processing assays The Journal of endocrinology Medium 15283695

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1991 PC1 and PC2 are proprotein convertases capable of cleaving proopiomelanocortin at distinct pairs of basic residues. Proceedings of the National Academy of Sciences of the United States of America 596 2023902
1995 Membrane glycoprotein PC-1 and insulin resistance in non-insulin-dependent diabetes mellitus. Nature 288 7830796
2002 Disruption of PC1/3 expression in mice causes dwarfism and multiple neuroendocrine peptide processing defects. Proceedings of the National Academy of Sciences of the United States of America 271 12145326
1992 Distribution and regulation of the prohormone convertases PC1 and PC2 in the rat pituitary. Molecular endocrinology (Baltimore, Md.) 261 1316544
2001 PC-1 nucleoside triphosphate pyrophosphohydrolase deficiency in idiopathic infantile arterial calcification. The American journal of pathology 236 11159191
2008 Common nonsynonymous variants in PCSK1 confer risk of obesity. Nature genetics 226 18604207
1993 The prohormone convertases PC1 and PC2 mediate distinct endoproteolytic cleavages in a strict temporal order during proopiomelanocortin biosynthetic processing. The Journal of biological chemistry 226 8380577
1993 Comparative biosynthesis, covalent post-translational modifications and efficiency of prosegment cleavage of the prohormone convertases PC1 and PC2: glycosylation, sulphation and identification of the intracellular site of prosegment cleavage of PC1 and PC2. The Biochemical journal 187 8397508
2003 Linked deficiencies in extracellular PP(i) and osteopontin mediate pathologic calcification associated with defective PC-1 and ANK expression. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 158 12817751
1992 Proprotein conversion is determined by a multiplicity of factors including convertase processing, substrate specificity, and intracellular environment. Cell type-specific processing of human prorenin by the convertase PC1. The Journal of biological chemistry 155 1597471
2000 Regulation of pancreatic PC1 and PC2 associated with increased glucagon-like peptide 1 in diabetic rats. The Journal of clinical investigation 139 10749575
1998 Ecto-phosphodiesterase/pyrophosphatase of lymphocytes and non-lymphoid cells: structure and function of the PC-1 family. Immunological reviews 131 9553761
1994 The developmental expression in rat of proteases furin, PC1, PC2, and carboxypeptidase E: implications for early maturation of proteolytic processing capacity. The Journal of neuroscience : the official journal of the Society for Neuroscience 125 8046441
1993 Ontogeny of the prohormone convertases PC1 and PC2 in the mouse hypophysis and their colocalization with corticotropin and alpha-melanotropin. Proceedings of the National Academy of Sciences of the United States of America 124 8389457
2016 PCSK1 Mutations and Human Endocrinopathies: From Obesity to Gastrointestinal Disorders. Endocrine reviews 118 27187081
1995 Proprotein convertases (PC1/PC3 and PC2) in normal and neoplastic human tissues: their use as markers of neuroendocrine differentiation. The Journal of clinical endocrinology and metabolism 117 7829629
1993 Purification and characterization of the prohormone convertase PC1(PC3). The Journal of biological chemistry 116 8449925
2016 Deficiency in prohormone convertase PC1 impairs prohormone processing in Prader-Willi syndrome. The Journal of clinical investigation 115 27941249
2006 Obesity, hyperphagia and increased metabolic efficiency in Pc1 mutant mice. Human molecular genetics 111 16644867
1999 The cell biology of the prohormone convertases PC1 and PC2. Progress in nucleic acid research and molecular biology 110 10506829
1999 The subtilisin/kexin family of precursor convertases. Emphasis on PC1, PC2/7B2, POMC and the novel enzyme SKI-1. Annals of the New York Academy of Sciences 108 10816641
1997 Comparative analysis of expression of the proprotein convertases furin, PACE4, PC1 and PC2 in human lung tumours. British journal of cancer 108 9166946
2002 Isolation and characterization of VGF peptides in rat brain. Role of PC1/3 and PC2 in the maturation of VGF precursor. Journal of neurochemistry 96 12065665
2016 PCSK1 Variants and Human Obesity. Progress in molecular biology and translational science 88 27288825
1994 Expression of the murine plasma cell nucleotide pyrophosphohydrolase PC-1 is shared by human liver, bone, and cartilage cells. Regulation of PC-1 expression in osteosarcoma cells by transforming growth factor-beta. The Journal of clinical investigation 83 8040311
1994 Developmental expression of the prohormone convertases PC1 and PC2 in mouse pancreatic islets. Endocrinology 81 7925129
1995 Interleukin 1 beta suppresses transforming growth factor-induced inorganic pyrophosphate (PPi) production and expression of the PPi-generating enzyme PC-1 in human chondrocytes. Proceedings of the National Academy of Sciences of the United States of America 80 7479785
1993 Heterologous processing of prosomatostatin in constitutive and regulated secretory pathways. Putative role of the endoproteases furin, PC1, and PC2. The Journal of biological chemistry 79 8095501
2000 NEC1, a novel gene, highly expressed in nectary tissue of Petunia hybrida. The Plant journal : for cell and molecular biology 72 11135107
2003 Biological processing of the cocaine and amphetamine-regulated transcript precursors by prohormone convertases, PC2 and PC1/3. The Journal of biological chemistry 71 12584191
2008 Paired box 6 (PAX6) regulates glucose metabolism via proinsulin processing mediated by prohormone convertase 1/3 (PC1/3). Diabetologia 67 19034419
2020 The heteromeric PC-1/PC-2 polycystin complex is activated by the PC-1 N-terminus. eLife 66 33164752
1998 Proprotein convertase PC1/3-related peptides are potent slow tight-binding inhibitors of murine PC1/3 and Hfurin. The Journal of biological chemistry 66 9813073
2000 The SAAS granin exhibits structural and functional homology to 7B2 and contains a highly potent hexapeptide inhibitor of PC1. FEBS letters 64 10812060
1998 nec1, a gene conferring a necrogenic phenotype, is conserved in plant-pathogenic Streptomyces spp. and linked to a transposase pseudogene. Molecular plant-microbe interactions : MPMI 61 9768513
2007 A switch from prohormone convertase (PC)-2 to PC1/3 expression in transplanted alpha-cells is accompanied by differential processing of proglucagon and improved glucose homeostasis in mice. Diabetes 60 17698597
1996 Skeletal muscle content of membrane glycoprotein PC-1 in obesity. Relationship to muscle glucose transport. Diabetes 57 8826966
1999 Induction of integral membrane PAM expression in AtT-20 cells alters the storage and trafficking of POMC and PC1. The Journal of cell biology 55 9971741
2015 Contribution of common non-synonymous variants in PCSK1 to body mass index variation and risk of obesity: a systematic review and meta-analysis with evidence from up to 331 175 individuals. Human molecular genetics 54 25784503
2009 Association of variants in the PCSK1 gene with obesity in the EPIC-Norfolk study. Human molecular genetics 54 19528091
2002 Horizontal transfer of the plant virulence gene, nec1, and flanking sequences among genetically distinct Streptomyces strains in the Diastatochromogenes cluster. Applied and environmental microbiology 54 11823214
1995 Purification and characteristics of the candidate prohormone processing proteases PC2 and PC1/3 from bovine adrenal medulla chromaffin granules. The Journal of biological chemistry 54 7713926
2017 Next-generation sequencing of the monogenic obesity genes LEP, LEPR, MC4R, PCSK1 and POMC in a Norwegian cohort of patients with morbid obesity and normal weight controls. Molecular genetics and metabolism 53 28377240
2014 A nonsense loss-of-function mutation in PCSK1 contributes to dominantly inherited human obesity. International journal of obesity (2005) 53 24890885
1994 Gene organization of the mouse pro-hormone and pro-protein convertase PC1. DNA and cell biology 51 8011166
2021 GLP-1 receptor signaling increases PCSK1 and β cell features in human α cells. JCI insight 49 33554958
1992 The cDNA sequence of the human pro-hormone and pro-protein convertase PC1. DNA and cell biology 49 1605851
1991 The plasma cell membrane glycoprotein, PC-1, is a threonine-specific protein kinase stimulated by acidic fibroblast growth factor. The Journal of biological chemistry 49 1715869
1991 Chromosomal assignments of the genes for neuroendocrine convertase PC1 (NEC1) to human 5q15-21, neuroendocrine convertase PC2 (NEC2) to human 20p11.1-11.2, and furin (mouse 7[D1-E2] region). Genomics 49 1765368
2022 Natural History of Obesity Due to POMC, PCSK1, and LEPR Deficiency and the Impact of Setmelanotide. Journal of the Endocrine Society 48 35528826
2011 Association of type 2 diabetes susceptibility genes (TCF7L2, SLC30A8, PCSK1 and PCSK2) and proinsulin conversion in a Chinese population. Molecular biology reports 46 21437630
2010 Association of obesity risk SNPs in PCSK1 with insulin sensitivity and proinsulin conversion. BMC medical genetics 46 20534142
2023 The protein phosphatase PC1 dephosphorylates and deactivates CatC to negatively regulate H2O2 homeostasis and salt tolerance in rice. The Plant cell 45 37325884
1996 Prohormone convertases (PC1/3 and PC2) in rat and human pancreas and islet cell tumors: subcellular immunohistochemical analysis. Pathology international 45 8916141
2016 60 YEARS OF POMC: From the prohormone theory to pro-opiomelanocortin and to proprotein convertases (PCSK1 to PCSK9). Journal of molecular endocrinology 44 26762158
2019 PPIP5K2 and PCSK1 are Candidate Genetic Contributors to Familial Keratoconus. Scientific reports 43 31852976
1993 Expression of nucleotide pyrophosphatase and alkaline phosphodiesterase I activities of PC-1, the murine plasma cell antigen. Molecular immunology 43 7678057
2014 The association of common variants in PCSK1 with obesity: a HuGE review and meta-analysis. American journal of epidemiology 42 25355447
2012 Selection signature analysis implicates the PC1/PCSK1 region for chicken abdominal fat content. PloS one 42 22792402
2018 Pancreatic cancer-derived exosomes suppress the production of GIP and GLP-1 from STC-1 cells in vitro by down-regulating the PCSK1/3. Cancer letters 41 29800682
2014 Polycystin-1 regulates actin cytoskeleton organization and directional cell migration through a novel PC1-Pacsin 2-N-Wasp complex. Human molecular genetics 41 24385601
2014 PC1, a non-peptide PKR1-preferring antagonist, reduces pain behavior and spinal neuronal sensitization in neuropathic mice. Pharmacological research 41 25434589
2007 Streptomyces turgidiscabies secretes a novel virulence protein, Nec1, which facilitates infection. Molecular plant-microbe interactions : MPMI 41 17555268
1999 Phylogenetic Analysis of 16S rRNA Genes and PCR Analysis of the nec1 Gene from Streptomyces spp. Causing Common Scab, Pitted Scab, and Netted Scab in Finland. Phytopathology 41 18944717
1997 The integrity of the RRGDL sequence of the proprotein convertase PC1 is critical for its zymogen and C-terminal processing and for its cellular trafficking. The Biochemical journal 41 9307023
1998 Membrane glycoprotein PC-1 and insulin resistance. Molecular and cellular biochemistry 37 9609127
1995 Mutational analysis of PC1 (SPC3) in PC12 cells. 66-kDa PC1 is fully functional. The Journal of biological chemistry 36 7559585
2016 Functional and clinical relevance of novel and known PCSK1 variants for childhood obesity and glucose metabolism. Molecular metabolism 35 28271036
2012 Disruption of proprotein convertase 1/3 (PC1/3) expression in mice causes innate immune defects and uncontrolled cytokine secretion. The Journal of biological chemistry 34 22396549
2009 Common PCSK1 haplotypes are associated with obesity in the Chinese population. Obesity (Silver Spring, Md.) 34 19875984
1998 Proglucagon processing in an islet cell line: effects of PC1 overexpression and PC2 depletion. Endocrinology 31 9528943
1996 The inhibition of the insulin receptor by the receptor protein PC-1 is not specific and results from the hydrolysis of ATP. Diabetes 31 8666152
1999 Regulation of prohormone convertase 1 (PC1) by gp130-related cytokines. Molecular and cellular endocrinology 30 10630414
2008 Expression of PCSK1 (PC1/3), PCSK2 (PC2) and PCSK3 (furin) in mouse small intestine. Regulatory peptides 29 18706454
2007 A targeted deletion/insertion in the mouse Pcsk1 locus is associated with homozygous embryo preimplantation lethality, mutant allele preferential transmission and heterozygous female susceptibility to dietary fat. Developmental biology 28 17490633
2001 Partial silencing of the NEC1 gene results in early opening of anthers in Petunia hybrida. Molecular genetics and genomics : MGG 28 11405624
1996 Threonine autophosphorylation and nucleotidylation of the hepatic membrane protein PC-1. European journal of biochemistry 27 8917428
2017 PC1/3 Deficiency Impacts Pro-opiomelanocortin Processing in Human Embryonic Stem Cell-Derived Hypothalamic Neurons. Stem cell reports 26 28132887
2017 Metabolic regulation of GLP-1 and PC1/3 in pancreatic α-cell line. PloS one 26 29121068
2015 Molecular Consequences of Proprotein Convertase 1/3 (PC1/3) Inhibition in Macrophages for Application to Cancer Immunotherapy: A Proteomic Study. Molecular & cellular proteomics : MCP 26 26330543
1999 Role of PC-1 in the etiology of insulin resistance. Annals of the New York Academy of Sciences 26 10842664
1993 Immunocytochemical localization of the neuropeptide-synthesizing enzyme PC1 in AtT-20 cells. Neuroendocrinology 26 8115023
1985 Murine plasma cell membrane antigen PC-1: molecular cloning of cDNA and analysis of expression. Proceedings of the National Academy of Sciences of the United States of America 26 3001713
2023 Analytical performance of the FDA-cleared Parsortix® PC1 system. Journal of circulating biomarkers 25 37601320
2016 Intestinal Bile Acid Composition Modulates Prohormone Convertase 1/3 (PC1/3) Expression and Consequent GLP-1 Production in Male Mice. Endocrinology 25 26789236
2013 Exome sequencing finds a novel PCSK1 mutation in a child with generalized malabsorptive diarrhea and diabetes insipidus. Journal of pediatric gastroenterology and nutrition 25 24280991
2009 Functional and structural characterization of a dense core secretory granule sorting domain from the PC1/3 protease. Proceedings of the National Academy of Sciences of the United States of America 25 19376969
2005 Abnormal expression and processing of the proprotein convertases PC1 and PC2 in human colorectal liver metastases. BMC cancer 25 16293189
2004 Prohormone convertase 1 (PC1) processing and sorting: effect of PC1 propeptide and proSAAS. The Journal of endocrinology 25 15283695
2001 Regulation of prohormone convertase 1 (PC1) by thyroid hormone. American journal of physiology. Endocrinology and metabolism 25 11120670
2023 Fermentation profile, aerobic stability, and microbial community dynamics of corn straw ensiled with Lactobacillus buchneri PC-C1 and Lactobacillus plantarum PC1-1. Microbiological research 24 36812838
2019 c-Myc is a regulator of the PKD1 gene and PC1-induced pathogenesis. Human molecular genetics 24 30388220
2013 Functional consequences of a novel variant of PCSK1. PloS one 24 23383060
2020 Transcription factor Creb3l1 regulates the synthesis of prohormone convertase enzyme PC1/3 in endocrine cells. Journal of neuroendocrinology 23 32319174
2009 FGF2 stimulation of the pyrophosphate-generating enzyme, PC-1, in pre-osteoblast cells is mediated by RUNX2. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 23 19049325
2018 Plasma Cell Alloantigen 1 and IL-10 Secretion Define Two Distinct Peritoneal B1a B Cell Subsets With Opposite Functions, PC1high Cells Being Protective and PC1low Cells Harmful for the Growing Fetus. Frontiers in immunology 22 29868008
2015 Revisiting PC1/3 Mutants: Dominant-Negative Effect of Endoplasmic Reticulum-Retained Mutants. Endocrinology 22 26207343
2012 PCSK1 rs6232 is associated with childhood and adult class III obesity in the Mexican population. PloS one 22 22737226
2012 Pax6 directly down-regulates Pcsk1n expression thereby regulating PC1/3 dependent proinsulin processing. PloS one 22 23056534
2011 Modulation of PC1/3 activity by self-interaction and substrate binding. Endocrinology 22 21303942

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