Proprotein processing protease

Significantly, the approach of activity profiling for cysteine proteases has established cathepsin L as a new protease pathway for neuropeptide biosynthesis. Together with current knowledge in the field, these data demonstrate the existence of two distinct protease pathways for converting proneuropeptides into active peptide neurotransmitters and hormones. These dual pathways consist of the newly discovered cysteine protease pathway for proneuropeptide processing, which consists of cathepsin L followed by Arg/Lys aminopeptidase (aminopeptidase B), and the previously known proprotein convertase (PC) family of subtilisin-like proteases (15-17) that process proneuropeptides with carboxypeptidase E (Fig. 3). Elucidation of these two protease pathways resulted from the application of the biochemical criteria required for processing proteases. 

Soon after it was shown that ubiquitin is conjugated to proteins, it was determined that this was a reversible process and deubiquitinating enzymes, or DUBs, could remove ubiquitin from ubiquitinated proteins [18, 19]. As the genes for ubiquitin and ubiquitin-like proteins were identified it became clear that all ubiquitin family members were synthesized as proproteins and processed to reveal the C-terminal glycylglycine of the active proteins [20]. Based on this information, DUBs were defined as proteases that cleave at the C-terminus of ubiquitin or ubiquitin-like proteins to reverse conjugation to target proteins and also process the proproteins. 

Proteases are essential for the conversion of inactive proprotein precursors into the active neuropeptides. Two main protease pathways have been elucidated for processing proneuropeptides and hormones the recently discovered cysteine protease cathepsin L with aminopeptidase B and the well-established subtilisin-like serine proteases that consist of prohormone con-vertases 1 and 2 followed by carboxypeptidase E/H. Endogenous regulators modulate these two protease pathways as endogenous peptide inhibitors, activators, and in vivo secretory vesicle proteins. Neuropeptides in CSE (cerebrospinal fluid) in neurological diseases can monitor brain nervous activity because neuropeptides represent active neurotransmission (93, 94). 

The proteases involved in the processing of prohormones and many other cellular precursor molecules are called converting enzymes or convertases, e.g., KEX[1,2] proteins of yeast (34), human furin, and mPC[l,2] proteins (or mouse prohormone convertases) (35). These proprotein convertases commonly recognize and cut within a basic amino acid sequence motif -Lys/Arg-Arg. 

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