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

人类II型跨膜丝氨酸蛋白酶-2(TMPRSS6)主要在肝脏表达，是铁稳态的关键蛋白水解性调节因子。Mattritase-2抑制肝源性多肽荷尔蒙海普西丁的合成，调节血浆铁水平。作为海普西丁的负性调节因子，Mattritase-2控制铁的吸收，因此成为治疗原发性和继发性铁超负荷疾病的新靶点，以弥补海普西丁的不足。为了扩大对体内平衡铁平衡的了解，尤其是海普西丁的调节，了解Mattritase-2的生化特性是必不可少的。在这个项目中，我们将分析Mattritase-2活性的调节，主要是其复杂的激活机制的控制，以及内源性抑制物如kunitz型抑制剂对活性Mattritase-2的调节。为此，将应用基于活性的探针作为分子工具。对Mattritase-2的生化特性的新见解将被用来产生与Mattritase-2结合的基于库尼茨的多肽抑制剂，具有更好的亲和力和选择性。有效的Mattritase-2抑制剂针对导致铁超载的机制，扩大了铁超载疾病的治疗选择范围。

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.