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Description

Legumain (UniProt: Q99538, also known as EC: 3.4.22.34, Asparaginyl endopeptidase, AEP, Protease cysteine 1, Delta Secretase) is encoded by the LGMN (also known as PRSC1) gene (Gene ID: 5641) in human. AEP is a lysosomal endopeptidase that displays strict specificity for the hydrolysis of asparaginyl bonds and can simultaneously cleave both amyloid precursor protein (APP) and tau. It cleaves aspartyl bonds slowly, especially under acidic conditions. AEP is synthesized with a signal peptide (aa 1-17) and a propeptide (aa 324-433) that are cleaved off in the mature form. It exists a homodimer before removal of the propeptide and after autocatalytic processing exists as a monomer. In its zymogen form, the uncleaved propeptide blocks access to the active site. AEP is phosphorylated on serine 226 by serine-arginine protein kinase 2 (SRPK2), which accelerates its autocatalytic cleavage and enhances its enzymatic activity. The active form translocates to cytoplasm. In Alzheimer s disease brains AEP is reported to be highly phosphorylated. Depletion of AEP is shown to reduce amyloid peptide production and senile plaque formation in 5XFAD mouse brain that leads to restoration of synaptic activity and cognitive function. Three isoforms of AEP have been described that are produced by alternative splicing. (Ref.: Wang Z-H., et al. (2017). Mol. Cell 67(5), 812-825, Zhang, Z et al (2015). Nat. Commun. 6, p. 9762).