Department of Dermatology, University of Kiel, Kiel, Germany.
Institute of Biochemistry, University of Kiel, Olshausenstraße 40, Kiel, Germany.
J Mol Cell Biol. 2019 Dec 23;11(11):979-993. doi: 10.1093/jmcb/mjz008.
Dysregulation of the disintegrin-metalloproteinase ADAM10 may contribute to the development of diseases including tumorigenesis and Alzheimer's disease. The mechanisms underlying ADAM10 sheddase activation are incompletely understood. Here, we show that transient exposure of the negatively charged phospholipid phosphatidylserine (PS) is necessarily required. The soluble PS headgroup was found to act as competitive inhibitor of substrate cleavage. Overexpression of the Ca2+-dependent phospholipid scramblase Anoctamin-6 (ANO6) led to increased PS externalization and substrate release. Transfection with a constitutively active form of ANO6 resulted in maximum sheddase activity in the absence of any stimulus. Calcium-dependent ADAM10 activation could not be induced in lymphocytes of patients with Scott syndrome harbouring a missense mutation in ANO6. A putative PS-binding motif was identified in the conserved stalk region. Replacement of this motif resulted in strong reduction of sheddase activity. In conjunction with the recently described 3D structure of the ADAM10 extracellular domain, a model is advanced to explain how surface-exposed PS triggers ADAM10 sheddase function.
去整合素金属蛋白酶 ADAM10 的失调可能导致包括肿瘤发生和阿尔茨海默病在内的多种疾病的发生。ADAM10 脱落酶激活的机制尚不完全清楚。在这里，我们表明带负电荷的磷脂磷脂酰丝氨酸 (PS) 的短暂暴露是必需的。发现可溶的 PS 头基作为底物切割的竞争性抑制剂。Ca2+依赖性磷脂 scramblase Anoctamin-6 (ANO6) 的过表达导致 PS 外排和底物释放增加。用组成型活性形式的 ANO6 转染可导致在没有任何刺激的情况下最大程度地激活脱落酶。在患有 Scott 综合征的患者的淋巴细胞中，ANO6 中的错义突变不能诱导钙依赖性 ADAM10 激活。在保守的柄区中鉴定出一个假定的 PS 结合基序。该基序的替换导致脱落酶活性的强烈降低。结合最近描述的 ADAM10 细胞外结构域的 3D 结构，提出了一个模型来解释如何通过表面暴露的 PS 触发 ADAM10 脱落酶功能。
