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

人II型跨膜丝氨酸蛋白酶-2 （TMPRSS6）主要表达于肝脏，是铁稳态的关键蛋白水解调节因子。基质蛋白酶-2抑制肝源肽激素hepcidin的合成，调节血浆铁水平。作为hepcidin的负调节因子，matpase -2控制铁的吸收，因此作为治疗原发性和继发性铁超载疾病以中和hepcidin缺乏的新靶点而受到关注。为了扩大对体内铁平衡，特别是hepcidin调节的理解，了解基质酶-2的生化特性是必不可少的。本项目将分析基质酶-2活性的调控，主要是对其复杂激活机制的控制，以及内源性抑制剂如Kunitz-type抑制剂对活性基质酶-2的调节。为此，将应用基于活性的探针作为分子工具。对matripase -2生化特性的新见解将用于生成基于kunitz的肽抑制剂，这些抑制剂与matripase -2结合，具有更高的亲和力和选择性。有效的基质蛋白酶-2抑制剂靶向导致铁超载的机制，并扩大铁超载疾病的治疗选择的紧密谱。

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.