Dept. of Dermatology, University of Kiel, 24105 Kiel, Germany.
Dept. of Dermatology, University of Kiel, 24105 Kiel, Germany.
Biochim Biophys Acta Mol Cell Res. 2017 Nov;1864(11 Pt B):2082-2087. doi: 10.1016/j.bbamcr.2017.06.006. Epub 2017 Jun 15.
ADAM10 and ADAM17 are the best characterized members of the ADAM (A Disintegrin and Metalloproteinase) - family of transmembrane proteases. Both are involved diverse physiological and pathophysiological processes. ADAMs are known to be regulated by posttranslational mechanisms. However, emerging evidence indicates that the plasma membrane with its unique dynamic properties may additionally play an important role in controlling sheddase function.
Membrane events that could contribute to regulation of ADAM-function are summarized.
Surface expression of peptidolytic activity should be differentiated from ADAM-sheddase function since the latter additionally requires that the protease finds its substrate in the lipid bilayer. We propose that this is achieved through horizontal and vertical reorganization of membrane nanoarchitecture coordinately occurring at the sites of sheddase activation. Reshuffling of nanodomains thereby guides traffic of enzyme and substrate to each other. For ADAM17 phosphatidylserine exposure is required to then induce its shedding function.
The novel concept that physicochemical properties of the lipid bilayer govern the action of ADAM-proteases may be extendable to other functional proteins that act at the cell surface. This article is part of a Special Issue entitled: Proteolysis as a Regulatory Event in Pathophysiology edited by Stefan Rose-John.
ADAM10 和 ADAM17 是解整合素金属蛋白酶（ADAM）家族中研究得最透彻的成员。它们都参与了多种生理和病理生理过程。ADAMs 的调节受到翻译后机制的影响。然而，新出现的证据表明，具有独特动态特性的质膜可能在控制脱落酶功能方面发挥重要作用。
总结了可能有助于调节 ADAM 功能的膜事件。
肽酶活性的表面表达应与 ADAM 脱落酶功能区分开来，因为后者还要求蛋白酶在脂质双层中找到其底物。我们提出，这是通过在脱落酶激活部位协调发生的质膜纳米结构的水平和垂直重组来实现的。纳米域的重新排列从而引导酶和底物彼此之间的运输。对于 ADAM17，暴露磷脂酰丝氨酸随后诱导其脱落酶功能。
质膜的物理化学性质决定 ADAM 蛋白酶作用的新概念可能适用于其他在细胞表面起作用的功能蛋白。本文是由 Stefan Rose-John 编辑的题为“蛋白水解作为病理生理学中的调节事件”的特刊的一部分。
