PCSK1 encodes prohormone convertase 1/3 (PC1/3, neuroendocrine convertase 1, EC 3.4.21.93), a calcium-dependent subtilisin/kexin-like serine endoprotease of the regulated secretory pathway. It is made as an inactive zymogen whose propeptide is removed autocatalytically in the endoplasmic reticulum, after which the mature enzyme is sorted into dense-core secretory granules of neurons and of endocrine and enteroendocrine cells, where the acidic, calcium-rich lumen permits catalysis. There it cleaves prohormone and proneuropeptide precursors at paired basic residues, acting with the partially complementary convertase PC2 and the downstream carboxypeptidase CPE. Characterised substrates include proopiomelanocortin (cleaved to ACTH and beta-lipotropin, the obligatory step before alpha-MSH can be produced), proinsulin, proglucagon-derived peptides, pro-GHRH, proAgRP, prorenin, prodynorphin, proenkephalin and provasopressin; in human beta cells PC1/3 rather than PC2 carries out proinsulin conversion. Biallelic loss-of-function PCSK1 mutations cause a pleiotropic prohormone-processing disorder with neonatal malabsorptive diarrhoea, early-onset obesity, hypogonadotropic hypogonadism, hypoadrenalism, altered thyroid function and reactive hypoglycaemia with a raised proinsulin-to-insulin ratio, and common nonsynonymous variants (N221D, Q665E-S690T) are associated with polygenic obesity risk. Several disease alleles act by misfolding and endoplasmic-reticulum retention or degradation rather than by direct loss of catalytic residues.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004175 endopeptidase activity | IEA GO_REF:0000107 | MODIFY | Summary: Endopeptidase activity (IEA, orthologue transfer from mouse Pcsk1). Reason: Correct but one level too general. PCSK1 is a calcium-dependent subtilisin-like serine endoprotease (EC 3.4.21.93) and the serine-type child term is directly supported. Proposed replacements: serine-type endopeptidase activity Supporting Evidence: file:human/PCSK1/PCSK1-uniprot.txt Reaction=Release of protein hormones, neuropeptides and renin from their precursors, generally by hydrolysis of -Lys-Arg-|- bonds PMID:27187081 is a serine endoprotease that is involved in the processing of a variety of proneuropeptides and prohormones |
| GO:0004252 serine-type endopeptidase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Serine-type endopeptidase activity, phylogenetically inferred within the subtilisin/kexin proprotein convertase family (IBA). Reason: The core molecular function. PCSK1 is a subtilisin-like serine endoprotease that cleaves prohormone precursors at paired basic residues, and patient mutations measurably reduce its catalytic activity. Supporting Evidence: file:human/PCSK1/PCSK1-uniprot.txt Reaction=Release of protein hormones, neuropeptides and renin from their precursors, generally by hydrolysis of -Lys-Arg-|- bonds PMID:27187081 is a serine endoprotease that is involved in the processing of a variety of proneuropeptides and prohormones PMID:18604207 Functional analysis showed a significant impairment of the N221D-mutant PC1/3 protein catalytic activity |
| GO:0004252 serine-type endopeptidase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Serine-type endopeptidase activity (IEA, combining InterPro, orthologue and EC mappings). Reason: Consistent with the enzyme's assigned EC number and with direct activity measurements on wild-type and mutant protein. Supporting Evidence: file:human/PCSK1/PCSK1-uniprot.txt Reaction=Release of protein hormones, neuropeptides and renin from their precursors, generally by hydrolysis of -Lys-Arg-|- bonds PMID:18604207 Functional analysis showed a significant impairment of the N221D-mutant PC1/3 protein catalytic activity |
| GO:0004252 serine-type endopeptidase activity | ISS GO_REF:0000024 | ACCEPT | Summary: Serine-type endopeptidase activity (ISS from mouse Pcsk1). Reason: Core function, also established directly for the human enzyme. Supporting Evidence: file:human/PCSK1/PCSK1-uniprot.txt Reaction=Release of protein hormones, neuropeptides and renin from their precursors, generally by hydrolysis of -Lys-Arg-|- bonds PMID:27187081 is a serine endoprotease that is involved in the processing of a variety of proneuropeptides and prohormones |
| GO:0005576 extracellular region | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Is active in the extracellular region (IBA). Reason: A fraction of mature PC1/3 is secreted, so some extracellular activity is plausible, but the physiologically important processing happens inside the regulated secretory pathway, where the enzyme meets its prohormone substrates. Supporting Evidence: PMID:8397508 Secretion of glycosylated and sulphated PC1 (84 kDa) occurs about 30 min after the onset of biosynthesis file:human/PCSK1/PCSK1-uniprot.txt Cytoplasmic vesicle, secretory vesicle. Note=Localized in the secretion granules |
| GO:0005576 extracellular region | IDA PMID:8397508 Comparative biosynthesis, covalent post-translational modifi... | KEEP AS NON CORE | Summary: Located in the extracellular region (IDA, pulse-chase of PC1 biosynthesis and secretion). Reason: Directly observed secretion of mature, glycosylated and sulphated PC1, but secondary to the granule compartment in which prohormone cleavage occurs. Supporting Evidence: PMID:8397508 Secretion of glycosylated and sulphated PC1 (84 kDa) occurs about 30 min after the onset of biosynthesis |
| GO:0005576 extracellular region | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Extracellular region (IEA). Reason: Consistent with the observed secretion of a fraction of the enzyme; non-core. Supporting Evidence: PMID:8397508 Secretion of glycosylated and sulphated PC1 (84 kDa) occurs about 30 min after the onset of biosynthesis |
| GO:0006508 proteolysis | IEA GO_REF:0000120 | MODIFY | Summary: Proteolysis (IEA). Reason: Correct but uninformative at this level; the specific process is the limited, activating cleavage of peptide hormone precursors. Proposed replacements: peptide hormone processing Supporting Evidence: file:human/PCSK1/PCSK1-uniprot.txt Reaction=Release of protein hormones, neuropeptides and renin from their precursors, generally by hydrolysis of -Lys-Arg-|- bonds PMID:27187081 is a serine endoprotease that is involved in the processing of a variety of proneuropeptides and prohormones |
| GO:0006508 proteolysis | TAS PMID:9207799 Obesity and impaired prohormone processing associated with m... | MODIFY | Summary: Proteolysis (TAS, the first human PC1 deficiency report). Reason: The cited work identified defective prohormone processing in a patient, which is captured specifically by peptide hormone processing rather than by the general parent term. Proposed replacements: peptide hormone processing Supporting Evidence: PMID:9207799 suggestive of a defective prohormone processing by the endopeptidase, prohormone convertase 1 file:human/PCSK1/PCSK1-uniprot.txt Reaction=Release of protein hormones, neuropeptides and renin from their precursors, generally by hydrolysis of -Lys-Arg-|- bonds |
| GO:0007267 cell-cell signaling | TAS PMID:9207799 Obesity and impaired prohormone processing associated with m... | REMOVE | Summary: Cell-cell signaling (TAS). Reason: PCSK1 acts upstream of hormone signalling by maturing the precursors; it does not itself participate in cell-cell signalling. Its contribution is already captured by peptide hormone processing and hormone biosynthesis. Supporting Evidence: file:human/PCSK1/PCSK1-uniprot.txt Reaction=Release of protein hormones, neuropeptides and renin from their precursors, generally by hydrolysis of -Lys-Arg-|- bonds PMID:27187081 is a serine endoprotease that is involved in the processing of a variety of proneuropeptides and prohormones |
| GO:0008236 serine-type peptidase activity | IEA GO_REF:0000002 | MODIFY | Summary: Serine-type peptidase activity (IEA, InterPro2GO). Reason: Domain-level mapping to the parent term; the endopeptidase child is supported. Proposed replacements: serine-type endopeptidase activity Supporting Evidence: file:human/PCSK1/PCSK1-uniprot.txt Reaction=Release of protein hormones, neuropeptides and renin from their precursors, generally by hydrolysis of -Lys-Arg-|- bonds |
| GO:0016020 membrane | IBA GO_REF:0000033 | REMOVE | Summary: Is active in membrane (IBA, from the broader subtilisin-like protease family). Reason: Family-level propagation that reflects the membrane-anchored convertases (such as furin and bacterial/fungal members) rather than PCSK1, which is a soluble enzyme of the secretory granule lumen. Propagation Review Root cause: PROPAGATION BAD Failure modes: COMPARTMENT OR COMPLEX MISMATCH LINEAGE OR TAXON MISMATCH Supporting Evidence: file:human/PCSK1/PCSK1-uniprot.txt Cytoplasmic vesicle, secretory vesicle. Note=Localized in the secretion granules |
| GO:0016485 protein processing | IEA GO_REF:0000107 | MODIFY | Summary: Protein processing (IEA, orthologue transfer). Reason: Correct but generic; the substrates are prohormones and proneuropeptides, so peptide hormone processing is the appropriate specific term. Proposed replacements: peptide hormone processing Supporting Evidence: file:human/PCSK1/PCSK1-uniprot.txt Substrates include POMC, renin, oxytocin, vasopressin, enkephalin, dynorphin, somatostatin, insulin and AGRP PMID:27187081 is a serine endoprotease that is involved in the processing of a variety of proneuropeptides and prohormones |
| GO:0016486 peptide hormone processing | IBA GO_REF:0000033 | ACCEPT | Summary: Peptide hormone processing (IBA). Reason: Core biological process. PC1/3 performs the activating cleavages that convert POMC, proinsulin and other prohormones into bioactive peptides. Supporting Evidence: file:human/PCSK1/PCSK1-uniprot.txt Substrates include POMC, renin, oxytocin, vasopressin, enkephalin, dynorphin, somatostatin, insulin and AGRP PMID:2023902 PC1 cleaves POMC into corticotropin and beta-lipotropin PMID:32291281 By demonstrating that healthy human Ξ²-cells process proinsulin by PC1/3 but not PC2 |
| GO:0016486 peptide hormone processing | IEA GO_REF:0000107 | ACCEPT | Summary: Peptide hormone processing (IEA). Reason: Core process, directly supported in human tissue. Supporting Evidence: PMID:32291281 By demonstrating that healthy human Ξ²-cells process proinsulin by PC1/3 but not PC2 file:human/PCSK1/PCSK1-uniprot.txt Substrates include POMC, renin, oxytocin, vasopressin, enkephalin, dynorphin, somatostatin, insulin and AGRP |
| GO:0016486 peptide hormone processing | ISS GO_REF:0000024 | ACCEPT | Summary: Peptide hormone processing (ISS from rat Pcsk1). Reason: Core process; the human deficiency phenotype is an unprocessed-prohormone syndrome. Supporting Evidence: PMID:27187081 obesity, malabsorptive diarrhea, hypogonadotropic hypogonadism, altered thyroid and adrenal function, and impaired regulation of plasma glucose levels in association with elevated circulating proinsulin-to-insulin ratio PMID:9207799 suggestive of a defective prohormone processing by the endopeptidase, prohormone convertase 1 |
| GO:0030070 insulin processing | IDA PMID:32291281 Revisiting Proinsulin Processing: Evidence That Human Ξ²-Cell... | ACCEPT | Summary: Insulin processing (IDA, human islet pulse-chase and immunohistochemistry). Reason: Direct human evidence that PC1/3, and not PC2, performs proinsulin processing in beta cells; consistent with the elevated proinsulin-to-insulin ratio in patients. Supporting Evidence: PMID:32291281 By demonstrating that healthy human Ξ²-cells process proinsulin by PC1/3 but not PC2 PMID:32291281 suppression of PC1/3 blocked processing of proinsulin but not proglucagon PMID:27187081 obesity, malabsorptive diarrhea, hypogonadotropic hypogonadism, altered thyroid and adrenal function, and impaired regulation of plasma glucose levels in association with elevated circulating proinsulin-to-insulin ratio |
| GO:0030070 insulin processing | IEA GO_REF:0000107 | ACCEPT | Summary: Insulin processing (IEA, orthologue transfer). Reason: Consistent with the direct human evidence for the same step. Supporting Evidence: PMID:32291281 By demonstrating that healthy human Ξ²-cells process proinsulin by PC1/3 but not PC2 |
| GO:0030133 transport vesicle | IEA GO_REF:0000044 | MODIFY | Summary: Transport vesicle (IEA, UniProt subcellular-location mapping). Reason: The relevant compartment is the dense-core secretory granule of the regulated secretory pathway, where the enzyme is stored with its substrates, rather than transport vesicles generally. Proposed replacements: secretory granule Supporting Evidence: file:human/PCSK1/PCSK1-uniprot.txt Cytoplasmic vesicle, secretory vesicle. Note=Localized in the secretion granules PMID:8916141 the colocalization of PC1/3 and insulin, and that of PC2 and glucagon, were observed in the same secretory granules |
| GO:0030141 secretory granule | IDA PMID:8916141 Prohormone convertases (PC1/3 and PC2) in rat and human panc... | ACCEPT | Summary: Is active in the secretory granule (IDA, immunoelectron microscopy of rat and human pancreas). Reason: PC1/3 colocalises with insulin in the same dense-core granules, which is where the acidic, calcium-rich environment permits prohormone cleavage. Supporting Evidence: PMID:8916141 the colocalization of PC1/3 and insulin, and that of PC2 and glucagon, were observed in the same secretory granules file:human/PCSK1/PCSK1-uniprot.txt Cytoplasmic vesicle, secretory vesicle. Note=Localized in the secretion granules |
| GO:0030141 secretory granule | IEA GO_REF:0000107 | ACCEPT | Summary: Is active in the secretory granule (IEA). Reason: Consistent with the direct localisation data. Supporting Evidence: PMID:8916141 the colocalization of PC1/3 and insulin, and that of PC2 and glucagon, were observed in the same secretory granules file:human/PCSK1/PCSK1-uniprot.txt Cytoplasmic vesicle, secretory vesicle. Note=Localized in the secretion granules |
| GO:0034774 secretory granule lumen | IEA GO_REF:0000117 | ACCEPT | Summary: Secretory granule lumen (IEA, ARBA). Reason: PC1/3 is a soluble luminal enzyme of the dense-core granule, not a membrane protein. Supporting Evidence: file:human/PCSK1/PCSK1-uniprot.txt Cytoplasmic vesicle, secretory vesicle. Note=Localized in the secretion granules PMID:8916141 the colocalization of PC1/3 and insulin, and that of PC2 and glucagon, were observed in the same secretory granules |
| GO:0034774 secretory granule lumen | TAS Reactome:R-HSA-265301 | ACCEPT | Summary: Secretory granule lumen (TAS, Reactome insulin processing). Reason: Consistent with the compartment in which proinsulin conversion occurs. Supporting Evidence: PMID:8916141 the colocalization of PC1/3 and insulin, and that of PC2 and glucagon, were observed in the same secretory granules PMID:32291281 By demonstrating that healthy human Ξ²-cells process proinsulin by PC1/3 but not PC2 |
| GO:0034774 secretory granule lumen | TAS Reactome:R-HSA-422021 | ACCEPT | Summary: Secretory granule lumen (TAS, Reactome). Reason: As above. Supporting Evidence: PMID:8916141 the colocalization of PC1/3 and insulin, and that of PC2 and glucagon, were observed in the same secretory granules |
| GO:0042446 hormone biosynthetic process | IDA PMID:32291281 Revisiting Proinsulin Processing: Evidence That Human Ξ²-Cell... | ACCEPT | Summary: Hormone biosynthetic process (IDA, human islet proinsulin processing). Reason: The activating cleavage performed by PC1/3 is the step that generates the mature hormone, so the enzyme does part of the work of hormone biosynthesis. Supporting Evidence: PMID:32291281 By demonstrating that healthy human Ξ²-cells process proinsulin by PC1/3 but not PC2 PMID:2023902 PC1 cleaves POMC into corticotropin and beta-lipotropin PMID:34068683 it cleaves and hence activates a number of protein precursors that play a key role in energy homeostasis |
| GO:0042802 identical protein binding | IEA GO_REF:0000107 | UNDECIDED | Summary: Identical protein binding (IEA), transferred from mouse Pcsk1, from a study of the PC1/3 carboxy-terminal sorting domain (PMID:19376969); the abstract does not describe the self-association. Reason: The row is transferred from mouse Pcsk1, where it is a physical-interaction annotation from a structural and functional study of the carboxy-terminal sorting domain of PC1/3 (PMID:19376969). Only the abstract is available, and it does not describe the self-association on which the annotation rests, so neither the annotation nor the earlier suggestion that it reflects autocatalytic propeptide cleavage can be checked. An experimentally based annotation is not removed on an untested alternative reading, and the row is left undecided. Supporting Evidence: PMID:8397508 demonstrated that the onset of the conversions of pro-PC1 into PC1 PMID:34068683 the p.E345A mutation in PC1/3 resulted in a (near) normal autocatalytic proPC1/3 processing |
| GO:0043005 neuron projection | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Is active in neuron projection (IBA). Reason: PC1/3 is a neuroendocrine enzyme whose granules are transported into neurites, where proneuropeptide processing continues; plausible and supported at family level, but the compartment that defines the function is the granule lumen. Supporting Evidence: file:human/PCSK1/PCSK1-uniprot.txt Cytoplasmic vesicle, secretory vesicle. Note=Localized in the secretion granules PMID:27187081 is a serine endoprotease that is involved in the processing of a variety of proneuropeptides and prohormones |
| GO:0043043 peptide biosynthetic process | IEA GO_REF:0000107 | MODIFY | Summary: Peptide biosynthetic process (IEA). Reason: Misleadingly broad - this term's usual sense is translation. What PCSK1 does is generate bioactive peptides by limited proteolysis of precursors, which peptide hormone processing states correctly. Proposed replacements: peptide hormone processing Supporting Evidence: file:human/PCSK1/PCSK1-uniprot.txt Reaction=Release of protein hormones, neuropeptides and renin from their precursors, generally by hydrolysis of -Lys-Arg-|- bonds file:human/PCSK1/PCSK1-uniprot.txt Substrates include POMC, renin, oxytocin, vasopressin, enkephalin, dynorphin, somatostatin, insulin and AGRP |
| GO:0043043 peptide biosynthetic process | ISS GO_REF:0000024 | MODIFY | Summary: Peptide biosynthetic process (ISS). Reason: As above; the mechanism is proteolytic maturation, not peptide synthesis. Proposed replacements: peptide hormone processing Supporting Evidence: file:human/PCSK1/PCSK1-uniprot.txt Reaction=Release of protein hormones, neuropeptides and renin from their precursors, generally by hydrolysis of -Lys-Arg-|- bonds PMID:27187081 is a serine endoprotease that is involved in the processing of a variety of proneuropeptides and prohormones |
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Download this section (compressed HTML)Q: Which PC1/3 substrate in enteroendocrine cells accounts for the neonatal malabsorptive diarrhoea of PCSK1 deficiency, given that small-intestinal morphology and the proGIP/GIP and proglucagon/GLP-1 ratios were reported as normal in at least one patient's colonic tissue?
Q: How much of the obesity in PCSK1 deficiency is attributable to failed POMC processing in hypothalamic neurons as opposed to failed processing of other energy-balance substrates such as proAgRP, pro-GHRH and the proglucagon-derived peptides?
Q: Why do individual disease alleles differ so markedly in which tissue's substrate processing they impair, and is that explained by allele-specific endoplasmic-reticulum retention rather than by differences in intrinsic catalytic activity?
Experiment: Measure substrate-resolved processing (proinsulin, POMC, proAgRP, proGIP, proglucagon) in isogenic human iPSC-derived beta cells, hypothalamic neurons and enteroendocrine cells carrying a panel of patient PCSK1 alleles, separating protein abundance, folding and catalytic turnover for each allele.
Experiment: Test whether chemical or pharmacological chaperones that relieve endoplasmic-reticulum retention restore prohormone processing for misfolding PCSK1 alleles, using a cell-based reporter of paired-basic-residue cleavage.
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