Proprotein Convertases Process and Thereby Inactivate Formylglycine-generating Enzyme

Ennemann E, Radhakrishnan K, Mariappan M, Wachs M, Pringle TH, Schmidt B, Dierks T (2013)
Journal of Biological Chemistry 288(8): 5828-5839.

Journal Article | Published | English

No fulltext has been uploaded

Author
; ; ; ; ; ;
Abstract
Formylglycine-generating enzyme (FGE) post-translationally converts a specific cysteine in newly synthesized sulfatases to formylglycine (FGly). FGly is the key catalytic residue of the sulfatase family, comprising 17 nonredundant enzymes in human that play essential roles in development and homeostasis. FGE, a resident protein of the endoplasmic reticulum, is also secreted. A major fraction of secreted FGE is N-terminally truncated, lacking residues 34-72. Here we demonstrate that this truncated form is generated intracellularly by limited proteolysis mediated by proprotein convertase(s) (PCs) along the secretory pathway. The cleavage site is represented by the sequence RYSR72 down arrow, a motif that is conserved in higher eukaryotic FGEs, implying important functionality. Residues Arg-69 and Arg-72 are critical because their mutation abolishes FGE processing. Furthermore, residues Tyr-70 and Ser-71 confer an unusual property to the cleavage motif such that endogenous as well as overexpressed FGE is only partially processed. FGE is cleaved by furin, PACE4, and PC5a. Processing is disabled in furin-deficient cells but fully restored upon transient furin expression, indicating that furin is the major protease cleaving FGE. Processing by endogenous furin occurs mostly intracellularly, although also extracellular processing is observed in HEK293 cells. Interestingly, the truncated form of secreted FGE no longer possesses FGly-generating activity, whereas the unprocessed form of secreted FGE is active. As always both forms are secreted, we postulate that furin-mediated processing of FGE during secretion is a physiological means of higher eukaryotic cells to regulate FGE activity upon exit from the endoplasmic reticulum.
Publishing Year
ISSN
eISSN
PUB-ID

Cite this

Ennemann E, Radhakrishnan K, Mariappan M, et al. Proprotein Convertases Process and Thereby Inactivate Formylglycine-generating Enzyme. Journal of Biological Chemistry. 2013;288(8):5828-5839.
Ennemann, E., Radhakrishnan, K., Mariappan, M., Wachs, M., Pringle, T. H., Schmidt, B., & Dierks, T. (2013). Proprotein Convertases Process and Thereby Inactivate Formylglycine-generating Enzyme. Journal of Biological Chemistry, 288(8), 5828-5839.
Ennemann, E., Radhakrishnan, K., Mariappan, M., Wachs, M., Pringle, T. H., Schmidt, B., and Dierks, T. (2013). Proprotein Convertases Process and Thereby Inactivate Formylglycine-generating Enzyme. Journal of Biological Chemistry 288, 5828-5839.
Ennemann, E., et al., 2013. Proprotein Convertases Process and Thereby Inactivate Formylglycine-generating Enzyme. Journal of Biological Chemistry, 288(8), p 5828-5839.
E. Ennemann, et al., “Proprotein Convertases Process and Thereby Inactivate Formylglycine-generating Enzyme”, Journal of Biological Chemistry, vol. 288, 2013, pp. 5828-5839.
Ennemann, E., Radhakrishnan, K., Mariappan, M., Wachs, M., Pringle, T.H., Schmidt, B., Dierks, T.: Proprotein Convertases Process and Thereby Inactivate Formylglycine-generating Enzyme. Journal of Biological Chemistry. 288, 5828-5839 (2013).
Ennemann, Eva, Radhakrishnan, Karthikeyan, Mariappan, Malaiyalam, Wachs, Michaela, Pringle, Thomas H., Schmidt, Bernhard, and Dierks, Thomas. “Proprotein Convertases Process and Thereby Inactivate Formylglycine-generating Enzyme”. Journal of Biological Chemistry 288.8 (2013): 5828-5839.
This data publication is cited in the following publications:
This publication cites the following data publications:

3 Citations in Europe PMC

Data provided by Europe PubMed Central.

Generating aldehyde-tagged antibodies with high titers and high formylglycine yields by supplementing culture media with copper(II).
York D, Baker J, Holder PG, Jones LC, Drake PM, Barfield RM, Bleck GT, Rabuka D., BMC Biotechnol. 16(), 2016
PMID: 26911368
Reconstitution of Formylglycine-generating Enzyme with Copper(II) for Aldehyde Tag Conversion.
Holder PG, Jones LC, Drake PM, Barfield RM, Banas S, de Hart GW, Baker J, Rabuka D., J. Biol. Chem. 290(25), 2015
PMID: 25931126

36 References

Data provided by Europe PubMed Central.

Molecular basis of multiple sulfatase deficiency, mucolipidosis II/III and Niemann-Pick C1 disease - Lysosomal storage disorders caused by defects of non-lysosomal proteins.
Dierks T, Schlotawa L, Frese MA, Radhakrishnan K, von Figura K, Schmidt B., Biochim. Biophys. Acta 1793(4), 2009
PMID: 19124046
The Cambrian conundrum: early divergence and later ecological success in the early history of animals.
Erwin DH, Laflamme M, Tweedt SM, Sperling EA, Pisani D, Peterson KJ., Science 334(6059), 2011
PMID: 22116879
Arg-X-Lys/Arg-Arg motif as a signal for precursor cleavage catalyzed by furin within the constitutive secretory pathway.
Hosaka M, Nagahama M, Kim WS, Watanabe T, Hatsuzawa K, Ikemizu J, Murakami K, Nakayama K., J. Biol. Chem. 266(19), 1991
PMID: 1905715
Substrate cleavage analysis of furin and related proprotein convertases. A comparative study.
Remacle AG, Shiryaev SA, Oh ES, Cieplak P, Srinivasan A, Wei G, Liddington RC, Ratnikov BI, Parent A, Desjardins R, Day R, Smith JW, Lebl M, Strongin AY., J. Biol. Chem. 283(30), 2008
PMID: 18505722
'Shed' furin: mapping of the cleavage determinants and identification of its C-terminus.
Plaimauer B, Mohr G, Wernhart W, Himmelspach M, Dorner F, Schlokat U., Biochem. J. 354(Pt 3), 2001
PMID: 11237874
Characterization of posttranslational formylglycine formation by luminal components of the endoplasmic reticulum.
Fey J, Balleininger M, Borissenko LV, Schmidt B, von Figura K, Dierks T., J. Biol. Chem. 276(50), 2001
PMID: 11600503
Function and structure of a prokaryotic formylglycine-generating enzyme.
Carlson BL, Ballister ER, Skordalakes E, King DS, Breidenbach MA, Gilmore SA, Berger JM, Bertozzi CR., J. Biol. Chem. 283(29), 2008
PMID: 18390551
Site-specific chemical modification of recombinant proteins produced in mammalian cells by using the genetically encoded aldehyde tag.
Wu P, Shui W, Carlson BL, Hu N, Rabuka D, Lee J, Bertozzi CR., Proc. Natl. Acad. Sci. U.S.A. 106(9), 2009
PMID: 19202059
In vivo evidence that furin from hepatocytes inactivates PCSK9.
Essalmani R, Susan-Resiga D, Chamberland A, Abifadel M, Creemers JW, Boileau C, Seidah NG, Prat A., J. Biol. Chem. 286(6), 2011
PMID: 21147780

Export

0 Marked Publications

Open Data PUB

Web of Science

View record in Web of Science®

Sources

PMID: 23288839
PubMed | Europe PMC

Search this title in

Google Scholar