From furless to heartless—unraveling the diverse functions of cathepsin L.

Abstract

Cysteine proteases are enzymes that use a cysteine residue, activated by a histidine residue, to serve the role of the nucleophile that attacks the peptide bond. The prototype cysteine protease is papain, an enzyme purified from the fruit of the papaya. Why does the papaya need papain? It turns out that cysteine proteinases are involved in virtually every aspect of plant physiology and development. They play a role in development, senescence, programmed cell death, storage, and mobilization of germinal proteins and enable the plant to deal with various types of environmental stress. Mammalian proteases homologous to papain have been discovered, most notably the cathepsins, cysteine, or aspartyl proteases, which have a role in immune responses, cell survival, and death, and numerous other cell systems and processes. The cathepsin cysteine-based active site apparently arose independently at least twice in the course of evolution. For instance, the caspases are enzymes that play a major role in apoptosis and have active sites similar to papain. However, their structure is otherwise unrelated to cathepsins. Cysteine cathepsins are active in pericellular environments as soluble enzymes or are bound to cell surface receptors at the plasma membrane and possibly even within secretory vesicles, lysosomes, the cytosol, mitochondria, and within the nuclei of eukaryotic cells. The proteolytic actions performed by cysteine cathepsins are essential in the maintenance of homeostasis and depend heavily upon their correct sorting and trafficking within cells.