Cho Yongcheol, Park Dongeun, Kim Chungho
Department of Life Sciences, Korea University, Seoul 02841, Republic of Korea.
School of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea.
Biochem Biophys Res Commun. 2017 Aug 26;490(3):997-1003. doi: 10.1016/j.bbrc.2017.06.153. Epub 2017 Jun 27.
Ectodomain shedding regulates functions of many membrane proteins through the cleavage of their juxtamembrane region mainly by a disintegrin and metalloproteinase family proteinases. Tumor necrosis factor-alpha converting enzyme (TACE) is known to be responsible for phorbol myristate acetate (PMA)-induced shedding of various membrane proteins. How PMA regulates TACE-dependent shedding and how TACE exhibits substrate specificity without proteolysis of other membrane proteins are questionable. Here, we show that TACE can interact with an actin-binding protein, filamin, through 20th filamin repeat. We found that the interaction between TACE and filamin was increased by PMA treatment. In addition, loss of filamin or specific disruption of TACE-filamin interaction inhibited ectodomain shedding of representative TACE substrates, CD44 and amyloid protein precursor. From these data, we suggest that filamin may work as a scaffold that can recruit TACE and its substrates in a PMA-dependent manner to achieve substrate specificity for TACE.
胞外域脱落主要通过去整合素和金属蛋白酶家族蛋白酶切割许多膜蛋白的近膜区域来调节其功能。已知肿瘤坏死因子-α转化酶（TACE）负责佛波酯（PMA）诱导的各种膜蛋白脱落。PMA如何调节TACE依赖性脱落以及TACE如何在不蛋白水解其他膜蛋白的情况下表现出底物特异性仍存在疑问。在此，我们表明TACE可通过细丝蛋白的第20个重复序列与肌动蛋白结合蛋白细丝蛋白相互作用。我们发现PMA处理可增加TACE与细丝蛋白之间的相互作用。此外，细丝蛋白缺失或TACE-细丝蛋白相互作用的特异性破坏会抑制代表性TACE底物CD44和淀粉样蛋白前体的胞外域脱落。根据这些数据，我们认为细丝蛋白可能作为一种支架，能够以PMA依赖的方式募集TACE及其底物，从而实现TACE的底物特异性。
