Institute of Molecular Pharmacology, Medical Faculty, RWTH Aachen University, Aachen, Germany.
Institute of Biochemistry, Christian-Albrechts-University, Olshausenstr. 40, 24118, Kiel, Germany.
Biochem Biophys Res Commun. 2020 May 28;526(2):355-360. doi: 10.1016/j.bbrc.2020.03.093. Epub 2020 Mar 26.
Proteolytic processing of membrane proteins by A disintegrin and metalloprotease-17 (ADAM17) is a key regulatory step in many physiological and pathophysiological processes. This so-called shedding is essential for development, regeneration and immune defense. An uncontrolled ADAM17 activity promotes cancer development, chronic inflammation and autoimmune diseases. Consequently, the ADAM17 activity is tightly regulated. As a final trigger for the shedding event a phosphatidylserine (PS) flip to the outer leaflet of the cell membrane was recently described. PS interacts with the extracellular part of ADAM17, which results in the shedding event by shifting the catalytic domain towards the membrane close to the cleavage sites within ADAM17 substrates. Our data indicate that the intrinsic proteolytic activity of the catalytic domain is prerequisite for the shedding activity and constantly present. However, the accessibility for substrate cleavage sites is controlled on several levels. In this report, we demonstrate that the positioning of the catalytic domain towards the cleavage sites is a crucial part of the shedding process. This finding contributes to the understanding of the complex and multilayered regulation of ADAM17 at the cell surface.
膜蛋白的蛋白水解加工由解整合素和金属蛋白酶 17（ADAM17）完成，这是许多生理和病理生理过程的关键调节步骤。这种所谓的脱落对于发育、再生和免疫防御至关重要。不受控制的 ADAM17 活性会促进癌症发展、慢性炎症和自身免疫性疾病。因此，ADAM17 的活性受到严格调控。最近的研究表明，磷脂酰丝氨酸（PS）翻转到细胞膜的外叶是脱落事件的最终触发因素。PS 与 ADAM17 的细胞外部分相互作用，通过将催化结构域向靠近 ADAM17 底物中的切割位点的膜移动，导致脱落事件。我们的数据表明，催化结构域的内在蛋白水解活性是脱落活性所必需的，并且始终存在。然而，底物切割位点的可及性受到多个层面的控制。在本报告中，我们证明了催化结构域朝向切割位点的定位是脱落过程的关键部分。这一发现有助于理解细胞表面 ADAM17 的复杂和多层次调节。
