Mild acidity likely accelerates the physiological matriptase autoactivation process: a comparative study between...

Area of Science:

• Biochemistry
• Molecular Biology
• Cell Biology

Background:

• Matriptase, a type 2 transmembrane serine protease, is crucial for pathophysiological functions.
• Its enzymatic activity is tightly regulated, with zymogen activation being a key control point.
• Activation generates the active enzyme and triggers inhibitory mechanisms like HAI-1 inhibition and shedding.

Purpose of the Study:

• To compare the structural requirements for spontaneous matriptase zymogen activation versus acid-induced activation.
• To systematically analyze the impact of 18 mutations on matriptase zymogen activation.
• To elucidate the physiological relevance of acid-induced matriptase activation.

Main Methods:

• Systematic mutational analysis of 18 different mutations in matriptase.
• Comparison of structural requirements for spontaneous and acid-induced zymogen activation.
• Assessment of matriptase zymogen activation in response to acidic conditions and spontaneous triggers.

Main Results:

• Both acid-induced and spontaneous matriptase activation are dependent on the structural integrity of the serine protease domain.
• Non-catalytic domains and posttranslational modifications are also essential for both activation modes.
• Mutations affecting structural integrity consistently impaired both spontaneous and acid-induced activation.

Conclusions:

• Acid-induced matriptase activation and spontaneous activation share common structural requirements.
• These findings suggest that acid-induced activation may be a physiological mechanism.
• Accelerating matriptase autoactivation, it could induce pericellular proteolysis.