Hansson Markus, Olsson Inge, Nauseef William M
Department of Hematology, C14, BMC, SE-221 84 Lund, Sweden.
Arch Biochem Biophys. 2006 Jan 15;445(2):214-24. doi: 10.1016/j.abb.2005.08.009. Epub 2005 Aug 31.
Exclusively synthesized by normal neutrophil and monocyte precursor cells, myeloperoxidase (MPO) functions not only in host defense by mediating efficient microbial killing but also can contribute to progressive tissue damage in chronic inflammatory states such as atherosclerosis. The biosynthetic precursor, apoproMPO, is processed slowly in the ER, undergoing cotranslational N-glycosylation, transient interactions with the molecular chaperones calreticulin and calnexin, and heme incorporation to generate enzymatically active proMPO that is competent for export into the Golgi. After exiting the Golgi the propeptide is removed prior to final proteolytic processing in azurophil granules, resulting in formation of a symmetric MPO homodimer linked by a disulfide bond. Some proMPO escapes granule targeting and becomes constitutively secreted to the extracellular environment. Although the precise mechanism is unknown, the pro-segment is required for normal processing and targeting, as propeptide-deleted MPO precursor is either degraded or constitutively secreted. Characterizing the molecular consequences of naturally occurring mutations that cause inherited MPO deficiency provides unique insight into the structural determinants of MPO involved in biosynthesis, processing and targeting.
髓过氧化物酶(MPO)仅由正常的中性粒细胞和单核细胞前体细胞合成,它不仅通过介导有效的微生物杀伤作用在宿主防御中发挥功能,而且在诸如动脉粥样硬化等慢性炎症状态下也会导致进行性组织损伤。生物合成前体脱辅基MPO在内质网中加工缓慢,经历共翻译N-糖基化、与分子伴侣钙网蛋白和钙连蛋白的短暂相互作用以及血红素掺入,以生成具有酶活性的前MPO,该前MPO能够输出到高尔基体。离开高尔基体后,前肽在嗜天青颗粒中进行最终蛋白水解加工之前被去除,从而形成由二硫键连接的对称MPO同二聚体。一些前MPO逃避颗粒靶向并组成性地分泌到细胞外环境中。尽管确切机制尚不清楚,但前肽段是正常加工和靶向所必需的,因为缺失前肽的MPO前体要么被降解,要么组成性分泌。对导致遗传性MPO缺乏的自然发生突变的分子后果进行表征,为深入了解MPO在生物合成、加工和靶向中所涉及的结构决定因素提供了独特的见解。