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The biology and therapeutic targeting of the proprotein convertases

Seidah, Nabil G., Prat, Annik·2012·Nature Reviews Drug Discovery
DOI 10.1038/nrd3699
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Abstract

The mammalian proprotein convertases constitute a family of nine secretory serine proteases that are related to bacterial subtilisin and yeast kexin. Seven of these (proprotein convertase 1 (PC1), PC2, furin, PC4, PC5, paired basic amino acid cleaving enzyme 4 (PACE4) and PC7) activate cellular and pathogenic precursor proteins by cleavage at single or paired basic residues, whereas subtilisin kexin isozyme 1 (SKI-1) and proprotein convertase subtilisin kexin 9 (PCSK9) regulate cholesterol and/or lipid homeostasis via cleavage at non-basic residues or through induced degradation of receptors. Proprotein convertases are now considered to be attractive targets for the development of powerful novel therapeutics. In this Review, we summarize the physiological functions and pathological implications of the proprotein convertases, and discuss proposed strategies to control some of their activities, including their therapeutic application and validation in selected disease states.

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  • Coexpression in HEK293 cells of human ASGR1 with each of the liver-expressed proprotein convertases revealed that only Furin can cleave the protein into a soluble approximately 28-kDa secreted form.

    “Coexpression in HEK293 cells of human ASGR1 with each of the liver-expressed PCs (26) revealed that only Furin can cleave the protein into a soluble ∼28-kDa secreted form (shed ASGR1; Fig. 11A).”

    From Asialoglycoprotein receptor 1 is a novel PCSK9-independent ligand of liver LDLR cleaved by furin (2021) · cites this paper as [26]

  • Furin, the third member of the proprotein convertase family, enhances the shedding of various cell-surface proteins at the general PC-like motif (R/K)Xn(R/K) down arrow.

    “Furin, the third member of the proprotein convertase (PC) family (26), has been shown to enhance the shedding of various cell-surface proteins at the general PC-like motif (R/K)Xn(R/K)↓, where Xn represents 0, 2, 4, or 6 spacer aa (27).”

    From Asialoglycoprotein receptor 1 is a novel PCSK9-independent ligand of liver LDLR cleaved by furin (2021) · cites this paper as [26]

  • The first seven members of the proprotein convertase family cleave substrates at the canonical motif R/K-Xn-R/K↓, where Xn = 0, 2, 4, or 6 spacer amino acids.

    “The first seven members of the family cleave substrates at the canonical motif R/K-Xn-R/K↓, where Xn = 0, 2, 4, or 6 spacer aa (26).”

    From Asialoglycoprotein receptor 1 is a novel PCSK9-independent ligand of liver LDLR cleaved by furin (2021) · cites this paper as [26]

  • SREBPs are proteolytically cleaved by the sequential activity of S1P and S2P in the Golgi.

    “where SREBPs are proteolytically cleaved by the sequential activity of S1P and S2P (encoded by MBTPS1 and MBTPS2, respectively)6,7”

    From Hepatic SREBP signaling requires SPRING to govern systemic lipid metabolism in mice and humans (2023) · cites this paper as [7]

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Metadata

Authors
Seidah, N. G., & Prat, A.
Venue
Nature Reviews Drug Discovery
Publisher
Springer Science and Business Media LLC
Published
2012-04-20
Volume
11
Issue
5
Pages
367-383
ISSN
  • 1474-1776
  • 1474-1784
DOI
10.1038/nrd3699
Cited by
759
References
7
Language
en
Licence
www.springer.com/tdm (tdm)

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