ADAM10 sheddase activation is controlled by cell membrane asymmetry
ADAM10 sheddase activation is controlled by cell membrane asymmetry
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DOI：
10.1093/jmcb/mjz008
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发表时间：
2019-11-01
影响因子：
5.5
通讯作者：
Reiss, Karina
中科院分区：
文献类型：
--
作者：
Bleibaum, Florian;Sommer, Anselm;Reiss, Karina
解整合素-金属蛋白酶ADAM 10的失调可能有助于包括肿瘤发生和阿尔茨海默病在内的疾病的发展。ADAM 10脱落酶激活的机制尚未完全了解。在这里，我们表明，瞬时暴露的带负电荷的磷脂磷脂酰丝氨酸（PS）是必要的。可溶性PS头基被发现作为底物裂解的竞争性抑制剂。过表达的钙离子依赖性磷脂爬酶Anoctamin-6（ANO 6）导致增加PS外化和底物释放。用组成型活性形式的ANO 6转染导致在没有任何刺激的情况下的最大脱落酶活性。钙依赖性的ADAM 10激活不能诱导斯科特综合征患者的淋巴细胞在ANO 6中的错义突变。一个假定的PS结合基序被确定在保守的茎区。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3D结构的ADAM 10胞外结构域，一个模型是先进的，以解释如何表面暴露的PS触发ADAM 10脱落酶功能。
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.