Mild acidity likely accelerates the physiological matriptase autoactivation process: a comparative study between
Bailing Jia1,2, Hamishi A Thompson2, Robert B Barndt2
1Department of Gastroenterology, Henan Provincial People's Hospital, Zhengzhou, 450003, China.
Abstract:
The pathophysiological functions of matriptase, a type 2 transmembrane serine protease, rely primarily on its enzymatic activity, which is under tight control through multiple mechanisms. Among those regulatory mechanisms, the control of zymogen activation is arguably the most important. Matriptase zymogen activation not only generates the mature active enzyme but also initiates suppressive mechanisms, such as rapid inhibition by HAI-1, and matriptase shedding. These tightly coupled events allow the potent matriptase tryptic activity to fulfill its biological functions at the same time as limiting undesired hazards. Matriptase is converted to the active enzyme via a process of autoactivation, in which the activational cleavage is thought to rely on the interactions of matriptase zymogen molecules and other as yet identified proteins. Matriptase autoactivation can occur spontaneously and is rapidly followed by the formation and then shedding of matriptase-HAI-1 complexes, resulting in the presence of relatively low levels of the complex on cells. Activation can also be induced by several non-protease factors, such as the exposure of cells to a mildly acidic buffer, which rapidly causes high-level matriptase zymogen activation in almost all cell lines tested. In the current study, the structural requirements for this acid-induced zymogen activation are compared with those required for spontaneous activation through a systematic analysis of the impact of 18 different mutations in various structural domains and motifs on matriptase zymogen activation. Our study reveals that both acid-induced matriptase activation and spontaneous activation depend on the maintenance of the structural integrity of the serine protease domain, non-catalytic domains, and posttranslational modifications. The common requirements of both modes of activation suggest that acid-induced matriptase activation may function as a physiological mechanism to induce pericellular proteolysis by accelerating matriptase autoactivation.
Insights
Matriptase (a serine protease) activation is tightly regulated. This study found that both spontaneous and acid-induced matriptase zymogen activation require structural integrity across its domains and modifications.
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.
