Proprotein convertase

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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. [1] Proprotein convertases have medical significance, because they are involved in many important biological processes, such as cholesterol synthesis. [2] 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. [3]

Contents

History

The phenomenon of prohormone conversion was discovered by Donald F. Steiner while examining the biosynthesis of insulin in 1967. [4] At the same time, while conducting chemical sequencing of β-lipotrophic hormone (βLPH) with sheep pituitary glands Dr. Michel Chretien determined the sequence of another hormone, melanocyte-stimulating hormone ( βMSH). [5] This was the chemical evidence, at the level of primary protein sequence that peptide hormones could be found within larger protein molecules. The identity of the responsible enzymes was not clear for decades. In 1984, David Julius, working in the laboratory of Jeremy Thorner, identified the product of the Kex2 gene as responsible for processing of the alpha factor mating pheromone. Robert Fuller, working with Thorner, identified the partial sequence of the Kex2-homologous Furin gene in 1989. In 1990 human Kex2-homologous genes were cloned by the Steiner group, Nabil Seidah and co-workers, Wim J.M. van de Ven and co-workers, Yukio Ikehara and co-workers, Randal Kaufman and co-workers, Gary Thomas and co-workers, and Kazuhisa Nakayama and co-workers.

Furin

One of the most well-known PPCs is furin. Furin is a serine endoprotease which cleaves protein precursors carboxyterminal of basic residues in motifs such as Arg–X–X–Arg and Lys/Arg–Arg. Cleavage usually results in activation of the proprotein but can also inactivate or modify the activity. Therefore, it is not surprising that it plays a major role in many physiological processes and pathologies, including cancer. [6] Some of its substrates are: proparathyroid hormone, transforming growth factor beta 1 precursor, proalbumin, pro-beta-secretase, membrane type-1 matrix metalloproteinase, beta subunit of pro-nerve growth factor and von Willebrand factor. A furin-like pro-protein convertase has been implicated in the processing of RGMc (also called hemojuvelin). Both the Ganz and Rotwein groups demonstrated that furin-like proprotein convertases (PPC) are responsible for conversion of 50 kDa HJV to a 40 kDa protein with a truncated COOH-terminus, at a conserved polybasic RNRR site. This suggests a potential mechanism to generate the soluble forms of HJV/hemojuvelin (s-hemojuvelin) found in the blood of rodents and humans. [7] [8]

Prohormone convertases

The two proprotein convertases that specialize in the processing of the precursors of peptide hormones and neuropeptides are also known in the field as "prohormone convertases". Both "prohormone convertase" and "proprotein convertase" are interchangeably abbreviated as "PC". PC1 (also known as PC3 and commonly referred to as PC1/3) and PC2 are the primary enzymes involved in the processing of the bioactive peptides precursors at paired basic residues. [9] PC1/3 and PC2 do not directly produce most neuropeptides and peptide hormones, but instead generate intermediates that contain C-terminal extensions of lysine and/or arginine residues; these are subsequently removed by carboxypeptidase E.

Clinical significance

Current scientific evidence indicates that both up- and down-regulation of the expression of proprotein convertases are part of the multiple changes occurring in gynecological tumors. PCs activate crucial substrates implicated in the progression of gynecological cancers, including adhesion molecules, metalloproteinases, and viral proteins. Experimental evidences suggest that careful targeting of PCs in gynecological cancer may represent a feasible strategy to deter tumor progression. [10] Variants of PCSK9 can reduce or increase circulating cholesterol. Furin plays a role in the activation of several different virus proteins, and inhibitors of furin have been explored as antiviral agents.

Biochemical structure

Kex2 was first purified and characterized by Charles Brenner and Robert Fuller in 1992. [11] The Kex2 crystal structure was solved by a group led by Dagmar Ringe, Robert Fuller and Gregory Petsko. That of Furin was determined by a group led by Manual Than and Wolfram Bode. The key features of Kex2 and Furin are a subtilisin-related catalytic domain, a specificity pocket that requires the amino acid amino terminal to the scissile bond to be arginine for rapid acylation, and a P-domain carboxy-terminal to the subtilisin domain, which is required for biosynthesis.

PCSK subtypes

To date there are 9 PCSKs with varying functions and tissue distributions. [12] Often, due to similar times of discovery from different groups the same PCSKs have acquired multiple names. In an attempt to alleviate confusion, there is a trend towards using the PCSK prefix with the appropriate number suffix. [13]

Current PCSK nomenclatureOther common names
PCSK1 PC1, PC3 (new name: PC1/3)
PCSK2 PC2
PCSK3 Furin, Pace, PC1
PCSK4 PC4
PCSK5 PC5, PC6 (new name: PC5/6)
PCSK6 PACE4
PCSK7 PC7, PC8
PCSK8 Site 1 Protease, S1P, SKI
PCSK9 NARC-1

Related Research Articles

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

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

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<span class="mw-page-title-main">Proprotein convertase 1</span>

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. PCSK1 and PCSK2 differentially cleave proopiomelanocortin and they act together to process proinsulin and proglucagon in pancreatic islets.

<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.

<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">Hemojuvelin</span>

Hemojuvelin (HJV), also known as repulsive guidance molecule C (RGMc) or hemochromatosis type 2 protein (HFE2), is a membrane-bound and soluble protein in mammals that is responsible for the iron overload condition known as juvenile hemochromatosis in humans, a severe form of hemochromatosis. In humans, the hemojuvelin protein is encoded by the HFE2 gene. Hemojuvelin is a member of the repulsive guidance molecule family of proteins. Both RGMa and RGMb are found in the nervous system, while hemojuvelin is found in skeletal muscle and the liver.

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

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<span class="mw-page-title-main">Neuromedin N</span> Chemical compound

Neuromedin N is a neuropeptide derived from the same precursor polypeptide as neurotensin, and with similar but subtly distinct expression and effects. Composed of the amino acid sequence Lys-Ile-Pro-Tyr-Ile-Leu, neuromedin N is homologous to neurotensin, both of whose sequences are found on the pro neurotensin/neuromedin N precursor C-terminus. Both sequences of neuromedin N as well as neurotensin are flanked by Lys-Arg amino acids, which comprise a consensus sequence for the endoprotease proprotein convertase. Neuromedin N is primarily synthesized in the neural and intestinal tissues of mammals; in studies performed in mice, neuromedin N's physiological effects were shown to include hypothermia and analgesia, arising from the peptide's ligand association to and interaction with neurotensin type 2 (NTS2) G protein-coupled receptors.

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">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">Oligopeptidase</span> Enzymes that cleaves peptides but not proteins

An Oligopeptidase is an enzyme that cleaves peptides but not proteins. This property is due to its structure: the active site of this enzyme is located at the end of a narrow cavity which can only be reached by peptides.

Carboxypeptidase D can refer to one of several enzymes. A family of serine carboxypeptidases includes is an enzyme. This enzyme has an optimal pH of 4.5-6.0, is inhibited by diisopropyl fluorophosphate, and catalyses the following chemical reaction

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.

References

  1. ↑ Andrew W. Artenstein; Steven M. Opal (December 29, 2011). "Proprotein Convertases in Health and Disease". N Engl J Med. 365 (26): 2507–2518. doi:10.1056/NEJMra1106700. PMID   22204726.
  2. ↑ New Drugs for Lipids Set Off Race, By ANDREW POLLACK, New York Times, November 5, 2012
  3. ↑ The Role of Proprotein Convertases in Animal Models of Skin Carcinogenesis, by Daniel Bassi, Morgan & Claypool Publishers, 2012, DOI: doi:10.4199/C00060ED1V01Y201206PAC001
  4. ↑ Steiner DF, Cunningham D, Spigelman L, Aten B (August 1967). "Insulin biosynthesis: evidence for a precursor". Science. 157 (3789): 697–700. Bibcode:1967Sci...157..697S. doi:10.1126/science.157.3789.697. PMID   4291105. S2CID   29382220.
  5. ↑ Chrétien M, Li CH (July 1967). "Isolation, purification, and characterization of gamma-lipotropic hormone from sheep pituitary glands". Can. J. Biochem. 45 (7): 1163–74. doi:10.1139/o67-133. PMID   6035976.
  6. ↑ Therapeutic Potential of Furin Inhibition: An Evaluation Using a Conditional Furin Knockout Mouse Model, by Jeroen Declercq and Prof. Dr. J.W.M. Creemers, Morgan & Claypool Publishers, 2012, DOI:10.4199/C00068ED1V01Y201211PAC004
  7. ↑ Lin L, Nemeth E, Goodnough JB, Thapa DR, Gabayan V, Ganz T (2008). "Soluble hemojuvelin is released by proprotein convertase-mediated cleavage at a conserved polybasic RNRR site". Blood Cells Mol. Dis. 40 (1): 122–31. doi:10.1016/j.bcmd.2007.06.023. PMC   2211380 . PMID   17869549.
  8. ↑ Kuninger D, Kuns-Hashimoto R, Nili M, Rotwein P (2008). "Pro-protein convertases control the maturation and processing of the iron-regulatory protein, RGMc/hemojuvelin". BMC Biochem. 9: 9. doi: 10.1186/1471-2091-9-9 . PMC   2323002 . PMID   18384687.
  9. ↑ Peptide Biosynthesis: Prohormone Convertases 1/3 and 2, by A. Hoshino and I. Lindberg, Morgan Claypool Publishers, 2012, ISBN   978-161504-364-4, DOI 10.4199/C00050ED1V01Y201112NPE001
  10. ↑ Proprotein Convertases in Gynecological Cancers, by A.J. Klein-Szanto, 2012, Morgan & Claypool Publishers, DOI:10.4199/C00068ED1V01Y201211PAC004
  11. ↑ Brenner C, Fuller RS (1992). "Structural and Enzymatic Characterization of a Purified Prohormone-Processing Enzyme: Secreted, Soluble Kex2 Protease". Proc. Natl. Acad. Sci. 89 (3): 922–926. Bibcode:1992PNAS...89..922B. doi: 10.1073/pnas.89.3.922 . PMC   48357 . PMID   1736307.
  12. ↑ Seidah NG, Chrétien M (November 1999). "Proprotein and prohormone convertases: a family of subtilases generating diverse bioactive polypeptides". Brain Res. 848 (1–2): 45–62. doi:10.1016/S0006-8993(99)01909-5. PMID   10701998. S2CID   22831526.
  13. ↑ Fugère M, Day R (June 2005). "Cutting back on pro-protein convertases: the latest approaches to pharmacological inhibition". Trends Pharmacol. Sci. 26 (6): 294–301. doi:10.1016/j.tips.2005.04.006. PMC   7119077 . PMID   15925704.
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