ArticleCell research2014
Structural analysis of asparaginyl endopeptidase reveals the activation mechanism and a reversible intermediate maturation stage.
Article in Cell research, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers.
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Who cites it
59 citing papers in PubMed, 99 citations in OpenAlex.
- Review
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- A protease-cleavable liposome for co-delivery of anti-PD-L1 and doxorubicin for colon cancer therapy in mice.Nature communications · 2025Article
- Post-translational cleavage generates truncated IgY forms in the snakeZoological research · 2025Article
- HIF2α drives ccRCC metastasis through transcriptional activation of methylation-controlled J protein and enhanced prolegumain secretion.Cell death & disease · 2025Article
- Asparagine endopeptidase regulates lysosome homeostasis via modulating endomembrane phosphoinositide composition.Cell death & disease · 2025Article
- Roles of C/EBPβ/AEP in Neurodegenerative Diseases.Current topics in medicinal chemistry · 2025Review
- Norepinephrine Drives Sleep Fragmentation Activation of Asparagine Endopeptidase, Locus Ceruleus Degeneration, and Hippocampal Amyloid-βThe Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- Complicated Role of Post-translational Modification and Protease-Cleaved Fragments of Tau in Alzheimer's Disease and Other Tauopathies.Molecular neurobiology · 2024Review
- Phage defence system CBASS is regulated by a prokaryotic E2 enzyme that imitates the ubiquitin pathway.Nature microbiology · 2024Article
- Leveraging yeast sequestration to study and engineer posttranslational modification enzymes.Biotechnology and bioengineering · 2024Review
- Murine Models of Secondary Cytokine Storm Syndromes.Advances in experimental medicine and biology · 2024Review
- On the design of a constitutively active peptide asparaginyl ligase for facile protein conjugation.FEBS open bio · 2023Article
- Role of LGMN in tumor development and its progression and connection with the tumor microenvironment.Frontiers in molecular biosciences · 2023Review
- The Mammalian Cysteine Protease Legumain in Health and Disease.International journal of molecular sciences · 2022Review
- Structural basis for proenzyme maturation, substrate recognition, and ligation by a hyperactive peptide asparaginyl ligase.The Plant cell · 2022Article
- Legumain Activity Is Controlled by Extended Active Site Residues and Substrate Conformation.International journal of molecular sciences · 2022Article
- Structural and functional studies of legumain-mycocypin complexes revealed a competitive, exosite-regulated mode of interaction.The Journal of biological chemistry · 2022Article
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Authors and funding
16 authors at 7 institutions in 2 countries.
Funding
Abstract
Asparaginyl endopeptidase (AEP) is an endo/lysosomal cysteine endopeptidase with a preference for an asparagine residue at the P1 site and plays an important role in the maturation of toll-like receptors 3/7/9. AEP is known to undergo autoproteolytic maturation at acidic pH for catalytic activation. Here, we describe crystal structures of the AEP proenzyme and the mature forms of AEP. Structural comparisons between AEP and caspases revealed similarities in the composition of key residues and in the catalytic mechanism. Mutagenesis studies identified N44, R46, H150, E189, C191, S217/S218 and D233 as residues that are essential for the cleavage of the peptide substrate. During maturation, autoproteolytic cleavage of AEP's cap domain opens up access to the active site on the core domain. Unexpectedly, an intermediate autoproteolytic maturation stage was discovered at approximately pH 4.5 in which the partially activated AEP could be reversed back to its proenzyme form. This unique feature was confirmed by the crystal structure of AEPpH4.5 (AEP was matured at pH 4.5 and crystallized at pH 8.5), in which the broken peptide bonds were religated and the structure was transformed back to its proenzyme form. Additionally, the AEP inhibitor cystatin C could be digested by the fully activated AEP, but could not be digested by activated cathepsins. Thus, we demonstrate for the first time that cystatins may regulate the activity of AEP through substrate competition for the active site.
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