Department of Dermatology, University of Kiel, Kiel, Germany.
Department of Dermatology, University of Kiel, Kiel, Germany
Life Sci Alliance. 2019 Aug 27;2(5). doi: 10.26508/lsa.201900430. Print 2019 Oct.
ADAM17, prominent member of the "Disintegrin and Metalloproteinase" (ADAM) family, controls vital cellular functions through cleavage of transmembrane substrates. Several of these play central roles in oncogenesis and inflammation, yet despite its importance, the mechanism by which ADAM17 is activated is not fully understood. We recently presented evidence that surface exposure of phosphatidylserine (PS) is the penultimate event required for sheddase activation, which occurs upon binding of a membrane-proximal, cationic binding motif to the anionic phospholipid headgroup. Here, we show that mutagenesis of the 3 amino acids constituting the PS-binding motif leads to embryonic lethality in mice. Heterozygotes showed no abnormalities. Primary hepatocytes and fibroblasts were analysed and found to express the mutant protease on the cell surface. However, PMA-stimulated release of ADAM17 substrates was completely abolished. The results directly support the novel concept of transiently externalised PS as essential trigger of extracellular protease function in vivo.
ADAM17 是“解整合素金属蛋白酶”（ADAM）家族的重要成员，通过切割跨膜底物来控制重要的细胞功能。这些底物中有几种在肿瘤发生和炎症中起着核心作用，但尽管其重要性，ADAM17 的激活机制仍未完全了解。我们最近的研究表明，磷脂酰丝氨酸（PS）的表面暴露是剪切酶激活的倒数第二个事件，该事件发生在膜近端的阳离子结合基序与阴离子磷脂头部基团结合时。在这里，我们展示了构成 PS 结合基序的 3 个氨基酸的突变导致小鼠胚胎致死。杂合子没有异常。对原代肝细胞和成纤维细胞进行分析，发现突变蛋白酶在细胞表面表达。然而，PMA 刺激的 ADAM17 底物的释放完全被阻断。这些结果直接支持了 PS 瞬时外向化为体内细胞外蛋白酶功能的关键触发因素的新概念。
