Phosphatidylserine exposure is required for ADAM17 sheddase function.
Phosphatidylserine exposure is required for ADAM17 sheddase function.
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DOI：
10.1038/ncomms11523
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发表时间：
2016-05-10
影响因子：
16.6
通讯作者：
Reiss K
中科院分区：
文献类型：
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作者：
Sommer A;Kordowski F;Büch J;Maretzky T;Evers A;Andrä J;Düsterhöft S;Michalek M;Lorenzen I;Somasundaram P;Tholey A;Sönnichsen FD;Kunzelmann K;Heinbockel L;Nehls C;Gutsmann T;Grötzinger J;Bhakdi S;Reiss K
ADAM17 是“解整合素和金属蛋白酶”(ADAM) 家族的重要成员，通过跨膜底物的裂解控制重要的细胞功能。在这里，我们提供的证据表明，磷脂酰丝氨酸 (PS) 的表面暴露对于 ADAM17 发挥脱落酶活性至关重要。 PS 暴露与多种 ADAM17 激活剂引起的底物脱落紧密相关。 PS依赖性表现在以下方面：(a)在经历凋亡的Raji细胞中； (b) 在具有可操纵 PS 含量的突变 PSA-3 细胞中； (c) 在斯科特综合征中，淋巴细胞在响应细胞内 Ca2+ 升高而外化 PS 的能力方面从遗传上丧失了能力。可溶性磷酸丝氨酸而非磷酸胆碱抑制底物裂解。 ADAM17 的分离膜近端结构域 (MPD) 与 PS 结合，但不与磷脂酰胆碱脂质体结合。在该结构域中鉴定出阳离子 PS 结合基序，替换该基序会消除脂质体结合并使蛋白酶无法切割细胞中的底物。我们推测表面暴露的 PS 将蛋白酶引导至其目标，然后在那里执行其脱落功能。 ADAM17 是蛋白酶“解整合素和金属蛋白酶”家族的成员，可从细胞表面裂解跨膜底物。作者在此表明，ADAM17 脱落酶活性需要磷脂酰丝氨酸的表面暴露，这可能是通过将蛋白酶引导至其底物来实现的。
ADAM17, a prominent member of the ‘Disintegrin and Metalloproteinase' (ADAM) family, controls vital cellular functions through cleavage of transmembrane substrates. Here we present evidence that surface exposure of phosphatidylserine (PS) is pivotal for ADAM17 to exert sheddase activity. PS exposure is tightly coupled to substrate shedding provoked by diverse ADAM17 activators. PS dependency is demonstrated in the following: (a) in Raji cells undergoing apoptosis; (b) in mutant PSA-3 cells with manipulatable PS content; and (c) in Scott syndrome lymphocytes genetically defunct in their capacity to externalize PS in response to intracellular Ca2+ elevation. Soluble phosphorylserine but not phosphorylcholine inhibits substrate cleavage. The isolated membrane proximal domain (MPD) of ADAM17 binds to PS but not to phosphatidylcholine liposomes. A cationic PS-binding motif is identified in this domain, replacement of which abrogates liposome-binding and renders the protease incapable of cleaving its substrates in cells. We speculate that surface-exposed PS directs the protease to its targets where it then executes its shedding function. ADAM17 is a member of the ‘Disintegrin and Metalloproteinase' family of proteases, that cleaves transmembrane substrates from the surfaces of cells. Here the authors show that surface exposure of phosphatidylserine is required for ADAM17 sheddase activity, possibly by directing the protease to its substrates.