Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Human, enzymes, proteases, propeptides, latency, activation, DIPEPTIDYL PEPTIDASE-I, HEPATOCYTE GROWTH-FACTOR, TYPE-1 MATRIX-METALLOPROTEINASE, HUMAN PROCATHEPSIN-B, GELATINASE B/MATRIX METALLOPROTEINASE-9, TRANSMEMBRANE SERINE-PROTEASE, KALLIKREIN-RELATED PEPTIDASES, PROPROTEIN CONVERTASE FURIN, TISSUE-SPECIFIC EXPRESSION, PROSTATE-SPECIFIC ANTIGEN, Amino Acid Sequence, Biomarkers, Catalytic Domain, Enzyme Activation, Enzyme Precursors, Humans, Mutation, Peptide Hydrolases, Protein Folding, Protein Multimerization, Proteolysis, C16/17/010#54271312, 12Z0920N#55263163, 0601 Biochemistry and Cell Biology, 3101 Biochemistry and cell biology

Abstract:

Proteases are a diverse group of hydrolytic enzymes, ranging from single-domain catalytic molecules to sophisticated multi-functional macromolecules. Human proteases are divided into five mechanistic classes: aspartate, cysteine, metallo, serine and threonine proteases, based on the catalytic mechanism of hydrolysis. As a protective mechanism against uncontrolled proteolysis, proteases are often produced and secreted as inactive precursors, called zymogens, containing inhibitory N-terminal propeptides. Protease propeptide structures vary considerably in length, ranging from dipeptides and propeptides of about 10 amino acids to complex multifunctional prodomains with hundreds of residues. Interestingly, sequence analysis of the different protease domains has demonstrated that propeptide sequences present higher heterogeneity compared with their catalytic domains. Therefore, we suggest that protease inhibition targeting propeptides might be more specific and have less off-target effects than classical inhibitors. The roles of propeptides, besides keeping protease latency, include correct folding of proteases, compartmentalization, liganding, and functional modulation. Changes in the propeptide sequence, thus, have a tremendous impact on the cognate enzymes. Small modifications of the propeptide sequences modulate the activity of the enzymes, which may be useful as a therapeutic strategy. This review provides an overview of known human proteases, with a focus on the role of their propeptides. We review propeptide functions, activation mechanisms, and possible therapeutic applications.