Characterization of the key role of the membrane-bound type II transmembrane serine protease matriptase-2 in iron homeostasis

• Applicant: Dr. Marit Stirnberg
• Subject Area: Biochemistry
• Term: from 2013 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 229847932

The human type II transmembrane serine protease matriptase-2 (TMPRSS6), predominantly expressed in the liver, is a key proteolytic regulator of iron homeostasis. Matriptase-2 suppresses the synthesis of the liver-derived peptide hormone hepcidin, modulating the level of plasma iron. As a negative regulator of hepcidin, matriptase-2 controls iron absorption, and thus attracted much attention as a novel target to treat primary and secondary iron overload diseases to neutralize deficiency in hepcidin. In order to expand the understanding of homeostatic iron balance, particularly hepcidin regulation, knowledge about the biochemical properties of matriptase-2 is essential. In this project, the regulation of matriptase-2 activity, predominantly the control of its complex activation mechanism and the modulation of active matriptase-2 by endogenous inhibitors such as Kunitz-type inhibitors, will be analyzed. For this, activity-based probes as molecular tools will be applied. New insights into the biochemical properties of matriptase-2 will be used to generate Kunitz-based peptide inhibitors binding to matriptase-2 with improved affinity and selectivity. Effective matriptase-2 inhibitors target the mechanism leading to iron overload and expand the tight spectrum of therapeutic option for iron overload diseases.

• DFG Programme: Research Grants