Proprotein convertase
Proprotein convertases 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]
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 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 nomenclature | Other 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 |
References
- ^ Andrew W. Artenstein and Steven M. Opal (December 29, 2011). "Proprotein Convertases in Health and Disease". N Engl J Med. 365: 2507–2518. doi:10.1056/NEJMra1106700.
{{cite journal}}: Cite has empty unknown parameter:|coauthors=(help) - ^ New Drugs for Lipids Set Off Race, By ANDREW POLLACK, New York Times, November 5, 2012
- ^ The Role of Proprotein Convertases in Animal Models of Skin Carcinogenesis, by Daniel Bassi, Morgan & Claypool Publishers, 2012, DOI: doi:10.4199/C00060ED1V01Y201206PAC001
- ^ Steiner DF, Cunningham D, Spigelman L, Aten B (August 1967). "Insulin biosynthesis: evidence for a precursor". Science. 157 (3789): 697–700. doi:10.1126/science.157.3789.697. PMID 4291105.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ 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.
- ^ 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
- ^ 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.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ 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.
{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link) - ^ 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
- ^ Proprotein Convertases in Gynecological Cancers, by A.J. Klein-Szanto, 2012, Morgan & Claypool Publishers, DOI:10.4199/C00068ED1V01Y201211PAC004
- ^ 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. doi:10.1073/pnas.89.3.922. PMC 48357. PMID 1736307.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ 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.
- ^ 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. PMID 15925704.
External links
- Protein Activation and Cancer eBook series
- Neuropeptides eBook series
- Proprotein+Convertases at the U.S. National Library of Medicine Medical Subject Headings (MeSH)