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Multistep autoactivation of asparaginyl endopeptidase in vitro and in vivo

Multistep autoactivation of asparaginyl endopeptidase in vitro and in vivo
Multistep autoactivation of asparaginyl endopeptidase in vitro and in vivo
Mammalian asparaginyl endopeptidase (AEP) or legumain is a recently discovered lysosomal cysteine protease that specifically cleaves after asparagine residues. How this unusually specific lysosomal protease is itself activated is not fully understood. Using purified recombinant pro-enzyme, we show that activation is autocatalytic, requires sequential removal of C- and N-terminal pro-peptides at different pH thresholds, and is bimolecular. Removal of the N-terminal propeptide requires cleavage after aspartic acid rather than asparagine. Cellular processing, either of exogenously added AEP precursor or of pulse-labeled endogenous precursor, introduces at least one further cleavage to yield the final mature lysosomal enzyme. We also provide evidence that in living cells, there is clear compartmental heterogeneity in terms of AEP activation status. Moreover, we show that human monocyte-derived dendritic cells harbor inactive proforms of AEP that become activated upon maturation of dendritic cells with lipopolysaccharide.
38980-38990
Li, Dongtao Ni
a868745e-38cb-425d-af11-6991ccdfe3b9
Matthews, Stephen P.
82dc8ef0-d4a6-4d04-a7c3-fbac3eb8cf20
Antoniou, Antony N.
3d711a3b-f688-46f9-823e-5bb925d10ea8
Mazzeo, Daniela
92b31a91-a630-4ad8-a7b5-ef0baa278738
Watts, Colin
29a9d995-5923-44b9-896b-e618a1ce2824
Li, Dongtao Ni
a868745e-38cb-425d-af11-6991ccdfe3b9
Matthews, Stephen P.
82dc8ef0-d4a6-4d04-a7c3-fbac3eb8cf20
Antoniou, Antony N.
3d711a3b-f688-46f9-823e-5bb925d10ea8
Mazzeo, Daniela
92b31a91-a630-4ad8-a7b5-ef0baa278738
Watts, Colin
29a9d995-5923-44b9-896b-e618a1ce2824

Li, Dongtao Ni, Matthews, Stephen P., Antoniou, Antony N., Mazzeo, Daniela and Watts, Colin (2003) Multistep autoactivation of asparaginyl endopeptidase in vitro and in vivo. The Journal of Biological Chemistry, 278 (40), 38980-38990. (doi:10.1074/jbc.M305930200).

Record type: Article

Abstract

Mammalian asparaginyl endopeptidase (AEP) or legumain is a recently discovered lysosomal cysteine protease that specifically cleaves after asparagine residues. How this unusually specific lysosomal protease is itself activated is not fully understood. Using purified recombinant pro-enzyme, we show that activation is autocatalytic, requires sequential removal of C- and N-terminal pro-peptides at different pH thresholds, and is bimolecular. Removal of the N-terminal propeptide requires cleavage after aspartic acid rather than asparagine. Cellular processing, either of exogenously added AEP precursor or of pulse-labeled endogenous precursor, introduces at least one further cleavage to yield the final mature lysosomal enzyme. We also provide evidence that in living cells, there is clear compartmental heterogeneity in terms of AEP activation status. Moreover, we show that human monocyte-derived dendritic cells harbor inactive proforms of AEP that become activated upon maturation of dendritic cells with lipopolysaccharide.

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Published date: 2003

Identifiers

Local EPrints ID: 26437
URI: http://eprints.soton.ac.uk/id/eprint/26437
PURE UUID: cf422b86-3b0e-49cb-94f6-4233498f2663

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Date deposited: 19 Apr 2006
Last modified: 15 Mar 2024 07:10

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Contributors

Author: Dongtao Ni Li
Author: Stephen P. Matthews
Author: Antony N. Antoniou
Author: Daniela Mazzeo
Author: Colin Watts

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