+ Site Statistics
+ Search Articles
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ PDF Full Text
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Translate
+ Recently Requested

Activation of the furin endoprotease is a multiple-step process: requirements for acidification and internal propeptide cleavage

Activation of the furin endoprotease is a multiple-step process: requirements for acidification and internal propeptide cleavage

Embo Journal 16(7): 1508-1518

Activation of furin requires autoproteolytic cleavage of its 83-amino acid propeptide at the consensus furin site, Arg-Thr-Lys-Arg107/. This RER-localized cleavage is necessary, but not sufficient, for enzyme activation. Rather, full activation of furin requires exposure to, and correct routing within, the TGN/endosomal system. Here, we identify the steps in addition to the initial propeptide cleavage necessary for activation of furin. Exposure of membrane preparations containing an inactive RER-localized soluble furin construct to either: (i) an acidic and calcium-containing environment characteristic of the TGN; or (ii) mild trypsinization at neutral pH, resulted in the activation of the endoprotease. Taken together, these results suggest that the pH drop facilitates the removal of a furin inhibitor. Consistent with these findings, following cleavage in the RER, the furin propeptide remains associated with the enzyme and functions as a potent inhibitor of the endoprotease. Co-immunoprecipitation studies coupled with analysis by mass spectrometry show that release of the propeptide at acidic pH, and hence activation of furin, requires a second cleavage within the autoinhibitory domain at a site containing a P6 arginine (-Arg70-Gly-Val-Thr-Lys-Arg75/-). The significance of this cleavage in regulating the compartment-specific activation of furin, and the relationship of the furin activation pathway to those of other serine endoproteases are discussed.

(PDF emailed within 0-6 h: $19.90)

Accession: 008102230

Download citation: RISBibTeXText

PMID: 9130696

DOI: 10.1093/emboj/16.7.1508

Related references

A truncated, secreted form of the furin/PACE endoprotease effects propeptide cleavage in CHO cell lines expressing recombinant human factor IX. Molecular Biology of the Cell 5(SUPPL ): 483A, 1994

Activation of human furin precursor processing endoprotease occurs by an intramolecular autoproteolytic cleavage. Journal of Biological Chemistry 267(20): 14304-8, 1992

Sequence of the complementary dna encoding rat furin a possible propeptide processing endoprotease. Nucleic Acids Research 18(22): 6719, 1990

Sequence of the cDNA encoding rat furin, a possible propeptide-processing endoprotease. Nucleic Acids Research 18(22): 6719-6719, 1990

Structural requirements for furin-induced cleavage and activation of Shiga toxin. Biochemical and Biophysical Research Communications 357(1): 144-149, 2007

Molecular and enzymatic properties of furin, a Kex2-like endoprotease involved in precursor cleavage at Arg-X-Lys/Arg-Arg sites. Journal of Biochemistry 111(3): 296-301, 1992

Influenza virus hemagglutinin with multibasic cleavage site is activated by furin, a subtilisin-like endoprotease. Embo Journal 11(7): 2407-2414, 1992

Cleavage of diphtheria toxin and the protective antigen of bacillus anthracis by the eukaryotic endoprotease furin. Abstracts of the General Meeting of the American Society for Microbiology 92: 31, 1992

Activation of pro-region chimeras of furin endoprotease. Journal of Cellular Biochemistry Supplement 0(19B): 244, 1995

Endoproteolytic cleavage of its propeptide is a prerequisite for efficient transport of furin out of the endoplasmic reticulum. Journal of Biological Chemistry 270(6): 2695-2702, 1995

A furin-like convertase mediates propeptide cleavage of BACE, the Alzheimer's beta -secretase. Journal of Biological Chemistry 275(48): 37712-7, 2000

Internal cleavages of the autoinhibitory prodomain are required for membrane type 1 matrix metalloproteinase activation, although furin cleavage alone generates inactive proteinase. Journal of Biological Chemistry 285(36): 27726-27736, 2010

Activation of an influenza virus A/turkey/Oregon/71 HA insertion variant by the subtilisin-like endoprotease furin. Virology 202(2): 988-991, 1994

Maturation of the trans-Golgi network protease furin: compartmentalization of propeptide removal, substrate cleavage, and COOH-terminal truncation. Journal of Cell Biology 127(6 Pt 2): 1829-1842, 1994

Identification of a pH sensor in the furin propeptide that regulates enzyme activation. Journal of Biological Chemistry 281(23): 16108-16116, 2006