Structure and function of legumain in health and disease

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.