Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany.
Washington University School of Medicine, Renal Division, St. Louis, MO, USA.
Sci Rep. 2016 Nov 23;6:37464. doi: 10.1038/srep37464.
Release of cytokines, growth factors and other life-essential molecules from precursors by a-disintegrin-and-metalloproteases (ADAMs) is regulated with high substrate-specificity. We hypothesized that this is achieved by cleavage-regulatory intracellular-domain (ICD)-modifications of the precursors. We show here that cleavage-stimuli-induced specific ICD-modifications cause structural substrate changes that enhance ectodomain sensitivity of neuregulin-1 (NRG1; epidermal-growth-factor) or CD44 (receptor-tyrosine-kinase (RTK) co-receptor) to chymotrypsin/trypsin or soluble ADAM. This inside-out signal transfer required substrate homodimerization and was prevented by cleavage-inhibitory ICD-mutations. In chimeras, regulation could be conferred to a foreign ectodomain, suggesting a common higher-order structure. We predict that substrate-specific protease-accessibility-regulation controls release of numerous ADAM substrates.
α- 解体素和金属蛋白酶 (ADAMs) 可从前体中释放细胞因子、生长因子和其他生命必需分子，其具有高度的底物特异性调控。我们假设，这是通过前体的裂解调控细胞内域 (ICD) 修饰来实现的。我们在这里表明，裂解刺激诱导的特异性 ICD 修饰导致结构底物变化，增强了神经调节蛋白 1 (NRG1；表皮生长因子) 或 CD44(受体酪氨酸激酶 (RTK) 共受体) 对糜蛋白酶/胰蛋白酶或可溶性 ADAM 的外域敏感性。这种由内而外的信号传递需要底物同源二聚化，并且被裂解抑制 ICD 突变所阻止。在嵌合体中，调控可以赋予外来的外域，表明存在共同的高级结构。我们预测，底物特异性蛋白酶可接近性调控控制着许多 ADAM 底物的释放。
