Proprotein convertase 1

Last updated
PCSK1
PDB 1kn6 EBI.jpg
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases PCSK1 , BMIQ12, NEC1, PC1, PC3, SPC3, proprotein convertase subtilisin/kexin type 1, PC1/3
External IDs OMIM: 162150 MGI: 97511 HomoloGene: 379 GeneCards: PCSK1
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001177876
NM_000439
NM_001177875

NM_013628

RefSeq (protein)

NP_000430
NP_001171346

NP_038656

Location (UCSC) Chr 5: 96.39 – 96.43 Mb Chr 13: 75.24 – 75.28 Mb
PubMed search [3] [4]
Wikidata
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proprotein convertase 1
Identifiers
EC no. 3.4.21.93
CAS no. 99676-46-7
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / QuickGO
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PMC articles
PubMed articles
NCBI proteins

Proprotein convertase 1, also known as prohormone convertase, prohormone convertase 3, or neuroendocrine convertase 1 and often abbreviated as PC1/3 is an enzyme that in humans is encoded by the PCSK1 gene. [5] PCSK1 and PCSK2 differentially cleave proopiomelanocortin and they act together to process proinsulin and proglucagon in pancreatic islets. [6]

Contents

Function

PC1/3 is an enzyme that performs the proteolytic cleavage of prohormones to their intermediate (or sometimes completely cleaved) forms. [6] It is present only in neuroendocrine cells such as brain, pituitary and adrenal, and most often cleaves after a pair of basic residues within prohormones but can occasionally cleave after a single arginine. It binds to a protein known as proSAAS, which also represents its endogenous inhibitor. PC1 is synthesized as a 99 kDa proform quickly converted to an 87 kDa major active form, which itself is nearly completely cleaved to a 66 kDa active form within neuroendocrine cells.

Proprotein convertase 1 is the enzyme largely responsible for the first step in the biosynthesis of insulin. Following the action of proprotein convertase 1, a carboxypeptidase is required to remove the basic residues from the processing intermediate and generate the bioactive form of insulin. Another prohormone convertase, proprotein convertase 2 plays a more minor role in the first step of insulin biosynthesis, but a greater role in the first step of glucagon biosynthesis. The knockout of proprotein convertase 1 is not lethal in mice or humans, most likely due to the presence of the second convertase, although mice lacking proprotein convertase 1 activity show a number of defects including slow growth.[ citation needed ]

Proprotein convertase 1 is a calcium (Ca2+) activated serine endoprotease (meaning that a serine residue is part of the active site that hydrolyzes the peptide bond within the substrate). It is related to the bacterial enzyme known as subtilisin. There are nine subtilisin homologs in mammals; in addition to proprotein convertase 1 and 2, other members of this enzyme family include furin, PACE4, PC4, PC5/6, PC7/8, PCSK9, and SKI1/S1P.

Proprotein convertase 1 converts prorenin into renin. [7]

Clinical significance

Variants in the PCSK1 gene may be associated with obesity. [8]

See also

Related Research Articles

<span class="mw-page-title-main">Proopiomelanocortin</span> Mammalian protein found in Homo sapiens

Pro-opiomelanocortin (POMC) is a precursor polypeptide with 241 amino acid residues. POMC is synthesized in corticotrophs of the anterior pituitary from the 267-amino-acid-long polypeptide precursor pre-pro-opiomelanocortin (pre-POMC), by the removal of a 26-amino-acid-long signal peptide sequence during translation. POMC is part of the central melanocortin system.

<span class="mw-page-title-main">Proinsulin</span> Precursor protein in humans

Proinsulin is the prohormone precursor to insulin made in the beta cells of the Pancreatic Islets, specialized regions of the pancreas. In humans, proinsulin is encoded by the INS gene. The pancreatic islets only secrete between 1% and 3% of proinsulin intact. However, because proinsulin has a longer half life than insulin, it can account for anywhere from 5–30% of the insulin-like structures circulating in the blood. There are higher concentrations of proinsulin after meals and lower levels when a person is fasting. Additionally, while proinsulin and insulin have structural differences, proinsulin does demonstrate some affinity for the insulin receptor. Due to the relative similarities in structure, proinsulin can produce between 5% and 10% of the metabolic activity similarly induced by insulin.

<span class="mw-page-title-main">Amylin</span> Peptide hormone that plays a role in glycemic regulation

Amylin, or islet amyloid polypeptide (IAPP), is a 37-residue peptide hormone. It is co-secreted with insulin from the pancreatic β-cells in the ratio of approximately 100:1 (insulin:amylin). Amylin plays a role in glycemic regulation by slowing gastric emptying and promoting satiety, thereby preventing post-prandial spikes in blood glucose levels.

<span class="mw-page-title-main">Furin</span> Enzyme found in humans

Furin is a protease, a proteolytic enzyme that in humans and other animals is encoded by the FURIN gene. Some proteins are inactive when they are first synthesized, and must have sections removed in order to become active. Furin cleaves these sections and activates the proteins. It was named furin because it was in the upstream region of an oncogene known as FES. The gene was known as FUR and therefore the protein was named furin. Furin is also known as PACE. A member of family S8, furin is a subtilisin-like peptidase.

Proprotein convertases (PPCs) are a family of proteins that activate other proteins. Many proteins are inactive when they are first synthesized, because they contain chains of amino acids that block their activity. Proprotein convertases remove those chains and activate the protein. The prototypical proprotein convertase is furin. Proprotein convertases have medical significance, because they are involved in many important biological processes, such as cholesterol synthesis. Compounds called proprotein convertase inhibitors can block their action, and block the target proteins from becoming active. Many proprotein convertases, especially furin and PACE4, are involved in pathological processes such as viral infection, inflammation, hypercholesterolemia, and cancer, and have been postulated as therapeutic targets for some of these diseases.

<span class="mw-page-title-main">Proprotein convertase 2</span> Protein-coding gene in the species Homo sapiens

Proprotein convertase 2 (PC2) also known as prohormone convertase 2 or neuroendocrine convertase 2 (NEC2) is a serine protease and proprotein convertase PC2, like proprotein convertase 1 (PC1), is an enzyme responsible for the first step in the maturation of many neuroendocrine peptides from their precursors, such as the conversion of proinsulin to insulin intermediates. To generate the bioactive form of insulin, a second step involving the removal of C-terminal basic residues is required; this step is mediated by carboxypeptidases E and/or D. PC2 plays only a minor role in the first step of insulin biosynthesis, but a greater role in the first step of glucagon biosynthesis compared to PC1. PC2 binds to the neuroendocrine protein named 7B2, and if this protein is not present, proPC2 cannot become enzymatically active. 7B2 accomplishes this by preventing the aggregation of proPC2 to inactivatable forms. The C-terminal domain of 7B2 also inhibits PC2 activity until it is cleaved into smaller inactive forms that lack carboxy-terminal basic residues. Thus, 7B2 is both an activator and an inhibitor of PC2. PC2 has been identified in a number of animals, including C. elegans.

<span class="mw-page-title-main">Bone morphogenetic protein 1</span> Mammalian protein found in Homo sapiens

Bone morphogenetic protein 1, also known as BMP1, is a protein which in humans is encoded by the BMP1 gene. There are seven isoforms of the protein created by alternate splicing.

<span class="mw-page-title-main">Carboxypeptidase E</span> Protein-coding gene in the species Homo sapiens

Carboxypeptidase E (CPE), also known as carboxypeptidase H (CPH) and enkephalin convertase, is an enzyme that in humans is encoded by the CPE gene. This enzyme catalyzes the release of C-terminal arginine or lysine residues from polypeptides.

<span class="mw-page-title-main">PCSK9</span> Mammalian protein found in humans

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme encoded by the PCSK9 gene in humans on chromosome 1. It is the 9th member of the proprotein convertase family of proteins that activate other proteins. Similar genes (orthologs) are found across many species. As with many proteins, PCSK9 is inactive when first synthesized, because a section of peptide chains blocks their activity; proprotein convertases remove that section to activate the enzyme. The PCSK9 gene also contains one of 27 loci associated with increased risk of coronary artery disease.

<span class="mw-page-title-main">Membrane-bound transcription factor site-1 protease</span> Mammalian protein found in Homo sapiens

Membrane-bound transcription factor site-1 protease, or site-1 protease (S1P) for short, also known as subtilisin/kexin-isozyme 1 (SKI-1), is an enzyme that in humans is encoded by the MBTPS1 gene. S1P cleaves the endoplasmic reticulum loop of sterol regulatory element-binding protein (SREBP) transcription factors.

Kexin is a prohormone-processing protease, specifically a yeast serine peptidase, found in the budding yeast. It catalyzes the cleavage of -Lys-Arg- and -Arg-Arg- bonds to process yeast alpha-factor pheromone and killer toxin precursors. The human homolog is PCSK4. It is a family of subtilisin-like peptidases. Even though there are a few prokaryote kexin-like peptidases, all kexins are eukaryotes. The enzyme is encoded by the yeast gene KEX2, and usually referred to in the scientific community as Kex2p. It shares structural similarities with the bacterial protease subtilisin. The first mammalian homologue of this protein to be identified was furin. In the mammal, kexin-like peptidases function in creating and regulating many differing proproteins.

<span class="mw-page-title-main">PCSK5</span> Protein-coding gene in the species Homo sapiens

Proprotein convertase subtilisin/kexin type 5 is an enzyme that in humans is encoded by the PCSK5 gene, found in chromosome 9q21.3 Two alternatively spliced transcripts are described for this gene but only one has its full length nature known.

<span class="mw-page-title-main">PCSK7</span> Protein-coding gene in the species Homo sapiens

Proprotein convertase subtilisin/kexin type 7 is an enzyme that in humans is encoded by the PCSK7 gene.

<span class="mw-page-title-main">PCSK6</span> Protein-coding gene in the species Homo sapiens

Proprotein convertase subtilisin/kexin type 6 is an protease that in humans is encoded by the PCSK6 gene which is located in chromosome 15. Pcsk6 is a calcium-dependent serine endoprotease that catalyzes the post-translational modification of precursor proteins from its ‘latent’ form to the cleaved ‘active’ form. Active Pcsk6 has been reported to process substrates such as transforming growth factor β, pro-albumin, von Willebrand factor, and corin. Clinically, Pcsk6 is suggested to play a role in left/right asymmetry, structural asymmetry of the brain, handedness, tumor progression, hemostasis, and cardiovascular diseases.

<span class="mw-page-title-main">SCG5</span> Protein-coding gene in humans

Neuroendocrine protein 7B2 is a protein that in humans is encoded by the SCG5 gene. The protein expressed by this gene is widely distributed in neuroendocrine tissues. It functions as a chaperone protein for the proprotein convertase PC2 by blocking the aggregation of this protein, and is required for the production of an active PC2 enzyme. It is an intrinsically disordered protein that may also function as a chaperone for other aggregating secretory proteins in addition to proPC2. 7B2 has been identified in vertebrates and in invertebrates as low as flatworms and insects. It is also called Sgne1 and Secretogranin V. In C. elegans, it was originally called e7B2 and then renamed Seven B Two. There is a Pfam entry for this protein: Secretogranin_V (PF05281).

<span class="mw-page-title-main">PCSK4</span> Protein-coding gene in the species Homo sapiens

Proprotein convertase subtilisin/kexin type 4 is an enzyme that in humans is encoded by the PCSK4 gene.

<span class="mw-page-title-main">Subtilase</span>

Subtilases are a family of subtilisin-like serine proteases. They appear to have independently and convergently evolved an Asp/Ser/His catalytic triad, like in the trypsin serine proteases. The structure of proteins in this family shows that they have an alpha/beta fold containing a 7-stranded parallel beta sheet.

A prohormone is a committed precursor of a hormone consisting of peptide hormones synthesized together that has a minimal hormonal effect by itself because of its expression-suppressing structure, often created by protein folding and binding additional peptide chains to certain ends, that makes hormone receptor binding sites located on its peptide hormone chain segments inaccessible. Prohormones can travel the blood stream as a hormone in an inactivated form, ready to be activated later in the cell by post-translational modification.

<span class="mw-page-title-main">Proprotein convertase subtilisin/kexin type 1 inhibitor</span> Mammalian protein found in Homo sapiens

Proprotein convertase subtilisin/kexin type 1 inhibitor is a protein by the name of proSAAS that in humans is encoded by the PCSK1N gene.

SERPIN A12

Serpin A12 is a glycoprotein that is a class A member of the serine protease inhibitor (serpin) family. In humans, Serpin A12 is encoded by the SERPINA12 gene.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000175426 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000021587 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Seidah NG, Mattei MG, Gaspar L, Benjannet S, Mbikay M, Chrétien M (September 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. 11 (1): 103–7. doi:10.1016/0888-7543(91)90106-O. PMID   1765368.
  6. 1 2 Jansen E, Ayoubi TA, Meulemans SM, Van de Ven WJ (June 1995). "Neuroendocrine-specific expression of the human prohormone convertase 1 gene. Hormonal regulation of transcription through distinct cAMP response elements". J. Biol. Chem. 270 (25): 15391–7. doi: 10.1074/jbc.270.25.15391 . PMID   7797529.
  7. "EC 3.4.21.93". www.qmul.ac.uk.
  8. Renström F, Payne F, Nordström A, et al. (April 2009). "Replication and extension of genome-wide association study results for obesity in 4923 adults from northern Sweden". Hum. Mol. Genet. 18 (8): 1489–96. doi:10.1093/hmg/ddp041. PMC   2664142 . PMID   19164386.