Membrane-Proximal Domain of a Disintegrin and Metalloprotease-17 Represents the Putative Molecular Switch of Its Shedding Activity Operated by Protein-disulfide Isomerase
Membrane-Proximal Domain of a Disintegrin and Metalloprotease-17 Represents the Putative Molecular Switch of Its Shedding Activity Operated by Protein-disulfide Isomerase
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DOI：
10.1021/ja400340u
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发表时间：
2013-04-17
影响因子：
15
通讯作者：
Lorenzen, Inken
中科院分区：
文献类型：
--
作者：
Duesterhoeft, Stefan;Jung, Sascha;Lorenzen, Inken
去整合素和金属蛋白酶-17（ADAM 17）是一种主要的脱落酶，负责调节广泛的生物过程，如细胞分化，再生或癌症进展。然而，调节ADAM 17的酶活性的机制知之甚少。最近，蛋白质二硫键异构酶（PDI）被证明与ADAM 17相互作用并下调其酶活性。在这里，我们通过NMR光谱和串联质谱证明PDI直接与膜近端结构域（MPD）相互作用，该结构域参与其二聚化和底物识别的ADAM 17。PDI催化MPD的硫氧还蛋白基序C600 XXC 603内的二硫键的异构化，并导致活性开放状态和非活性闭合构象之间的剧烈结构变化。MPD puplex的这种构象变化充当分子开关，促进ADAM 17中胞外结构域的全局重定向并调节其脱落活性。
A disintegrin and metalloprotease-17 (ADAM17) is a major sheddase responsible for the regulation of a wide range of biological processes, like cellular differentiation, regeneration, or cancer progression. Hitherto, the mechanism regulating the enzymatic activity of ADAM17 is poorly understood. Recently, protein-disulfide isomerase (PDI) was shown to interact with ADAM17 and to down-regulate its enzymatic activity. Here we demonstrate by NMR spectroscopy and tandem-mass spectrometry that PDI directly interacts with the membrane-proximal domain (MPD), a domain of ADAM17 involved in its dimerization and substrate recognition. PDI catalyzes an isomerization of disulfide bridges within the thioredoxin motif C600XXC603 of the MPD and results in a drastic structural change between an active open state and an inactive closed conformation. This conformational change of the MPD putatively acts as a molecular switch, facilitating a global reorientation of the extracellular domains in ADAM17 and regulating its shedding activity.