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

膜结合 II 型跨膜丝氨酸蛋白酶 matriptase-2 在铁稳态中关键作用的表征

• 批准号: 229847932
• 负责人: Dr. Marit Stirnberg
• 金额: --
• 依托单位: Pharmazeutisches Institut
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/229847932?language=en
• 关键词: Characterization; key; role; membrane; bound

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.

人II型跨膜丝氨酸蛋白酶matriptase-2（TMPRSS 6）主要在肝脏中表达，是铁稳态的关键蛋白水解调节剂。间质蛋白酶-2抑制肝源性肽激素铁调素的合成，调节血浆铁水平。作为铁调素的负调节因子，间质蛋白酶-2控制铁吸收，因此作为治疗原发性和继发性铁过载疾病以中和铁调素缺乏的新靶点而引起了广泛关注。为了扩大对稳态铁平衡，特别是铁调素调节的理解，关于间质蛋白酶-2的生化特性的知识是必不可少的。在该项目中，将分析间质蛋白酶-2活性的调节，主要是其复杂激活机制的控制和内源性抑制剂如Kunitz型抑制剂对活性间质蛋白酶-2的调节。为此，将应用基于活性的探针作为分子工具。对间质蛋白酶-2的生物化学性质的新见解将用于产生以改进的亲和力和选择性结合间质蛋白酶-2的基于Kunitz的肽抑制剂。有效的间质蛋白酶-2抑制剂靶向导致铁超负荷的机制，并扩大了铁超负荷疾病的治疗选择的范围。