Protease propeptide structures, mechanisms of activation, and functions

Area of Science:

• Biochemistry
• Enzymology
• Molecular Biology

Background:

• Proteases are essential hydrolytic enzymes classified into five mechanistic groups.
• They are often synthesized as inactive zymogens with N-terminal inhibitory propeptides to prevent uncontrolled activity.
• Propeptides exhibit significant sequence diversity compared to catalytic domains.

Purpose of the Study:

• To review human proteases, emphasizing the critical roles of their propeptides.
• To explore propeptide functions beyond latency, including folding, localization, and modulation.
• To discuss the therapeutic potential of targeting protease propeptides.

Main Methods:

• Literature review of human proteases and their propeptides.
• Analysis of propeptide sequence heterogeneity and functional diversity.
• Examination of activation mechanisms and therapeutic strategies targeting propeptides.

Main Results:

• Propeptides play crucial roles in protease folding, compartmentalization, and functional modulation.
• Propeptide sequences are highly variable, suggesting specificity in their interactions.
• Targeting propeptides may offer a more specific approach to protease inhibition with reduced off-target effects.

Conclusions:

• Propeptides are key regulators of protease activity and function.
• The heterogeneity of propeptides presents opportunities for developing highly specific therapeutic agents.
• Modulating propeptide sequences could be a viable strategy for enzyme-targeted therapies.