Structure and function of legumain in health and disease

Abstract

The last years have seen a steady increase in our understanding of legumain biology that is driven from two largely uncoupled research arenas, the mammalian and the plant legumain field. Research on legumain, which is also referred to as asparaginyl endopeptidase (AEP) or vacuolar processing enzyme (VPE), is slivered, however. Here we summarise recent important findings and put them into a common perspective. Legumain is usually associated with its cysteine endopeptidase activity in lysosomes where it contributes to antigen processing for class II MHC presentation. However, newly recognized functions disperse previously assumed boundaries with respect to their cellular compartmentalisation and enzymatic activities. Legumain is also found extracellularly and even translocates to the cytosol and the nucleus, with seemingly incompatible pH and redox potential. These different milieus translate into changes of legumain's molecular properties, including its (auto-)activation, conformational stability and enzymatic functions. Contrasting its endopeptidase activity, legumain can develop a carboxypeptidase activity which remains stable at neutral pH. Moreover, legumain features a peptide ligase activity, with intriguing mechanistic peculiarities in plant and human isoforms. In pathological settings, such as cancer or Alzheimer's disease, the proper association of legumain activities with the corresponding cellular compartments is breached. Legumain's increasingly recognized physiological and pathological roles also indicate future research opportunities in this vibrant field.

Asparagine endopeptidase cleaves α-synuclein and mediates pathologic activities in Parkinson's disease

“…These observations are consistent with findings from previous reports indicating that the lysosomal AEP penetrates into the cytoplasm in human AD brains and cleaves both tau and SET, a PP2A inhibitor, thereby mediating AD pathogenesis 26 . In fact, AEP has been found to be active in the near-neutral pH milieus of the cytosol, nucleus and cell surface 38 .…”

Counter Selection Substrate Library Strategy for Developing Specific Protease Substrates and Probes

“…Legumain (asparaginyl endopeptidase - AEP, EC 3.4.22.34) displays high selectivity and cleaves substrates after Asn (P1 position) (Chen et al, 1997; Chen et al, 2000; Dall and Brandstetter, 2016). However, at acid pH this enzyme can also hydrolyze peptide bonds after Asp, which overlaps with caspases substrate specificity (Dall and Brandstetter, 2012).…”

Cystatins, cysteine peptidase inhibitors, as regulators of immune cell cytotoxicity

“…Inside the cells it is present in the endosomal/lysosomal pathway, where it acts as an endopeptidase. However, legumain is also found in the cytosol, nucleus or extracellularly and, in addition to its endopeptidase activity, also acts as a carboxypeptidase and peptide ligase (5).…”

“…Among those peptidases involved in immune processes, many studies have been focused on a group of endosomal/lysosomal cysteine peptidases, the cysteine cathepsins, whose involvement in antigen processing and presentation, cytotoxicity of natural killer (NK) cells and cytotoxic T lymphocytes (CTL), migration and adhesion of immune cells, cytokine and growth factor regulation and toll like receptor (TLR) signalling have been demonstrated (3,4). In addition to cathepsins, another lysosomal cysteine peptidase, legumain or asparaginyl endopeptidase, has also been associated with the immune response, most notably with antigen presentation and TLR signalling (4,5). The activities of cysteine cathepsins and legumain are regulated on different levels.…”