Jagged-1 juxtamembrane region: Biochemical characterization and cleavage by ADAM17 (TACE) catalytic domain
Jagged-1 juxtamembrane region: Biochemical characterization and cleavage by ADAM17 (TACE) catalytic domain
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DOI：
10.1016/j.bbrc.2013.02.022
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发表时间：
2013-03-22
影响因子：
3.1
通讯作者：
Pintar, Alessandro
中科院分区：
文献类型：
--
作者：
Coglievina, Maristella;Guarnaccia, Corrado;Pintar, Alessandro
由ADAMs（一种分解素和金属蛋白酶）进行的膜受体和配体的外胞域脱落在包括Notch在内的几种信号通路中起重要作用。然而，对底物识别的依据却知之甚少。我们证明了与Notch配体之一Jagged-1的近膜区相对应的重组蛋白表现为一个结构化模块，并在El054处被ADAM17催化结构域切割。短合成肽在同一位点裂解，但速率高得多，这意味着天然蛋白中裂解位点的结构是底物识别的关键决定因素。我们还发现，E1054附近的Alagille综合征相关突变增加了卵裂率，这表明该突变可能导致Notch信号的不平衡，这是由于Jagged-1脱落水平较高。(C) 2013爱思唯尔公司版权所有。
Ectodomain shedding of membrane receptors and ligands carried out by ADAMs (A disintegrin and metalloprotease) plays a major role in several signaling pathways, including Notch. The grounds of substrate recognition, however, are poorly understood. We demonstrate that a recombinant protein corresponding to the juxtamembrane region of Jagged-1, one of the Notch ligands, behaves as a structured module and is cleaved by ADAM17 catalytic domain at El054. A short synthetic peptide is cleaved at the same site but at a much higher rate, implying that the structure of the cleavage site in the native protein is a key determinant for substrate recognition. We also show that an Alagille syndrome-associated mutation near E1054 increases the cleavage rate, which suggests that this mutation may lead to an unbalance in Notch signaling due to a higher level of Jagged-1 shedding. (C) 2013 Elsevier Inc. All rights reserved.