MRC Laboratory of Molecular Biology, Cambridge, UK.
Mol Cell. 2009 Dec 25;36(6):1048-59. doi: 10.1016/j.molcel.2009.11.006.
Members of the widespread rhomboid family of intramembrane proteases cleave transmembrane domain (TMD) proteins to regulate processes as diverse as EGF receptor signaling, mitochondrial dynamics, and invasion by apicomplexan parasites. However, lack of information about their substrates means that the biological role of most rhomboids remains obscure. Knowledge of how rhomboids recognize their substrates would illuminate their mechanism and might also allow substrate prediction. Previous work has suggested that rhomboid substrates are specified by helical instability in their TMD. Here we demonstrate that rhomboids instead primarily recognize a specific sequence surrounding the cleavage site. This recognition motif is necessary for substrate cleavage, it determines the cleavage site, and it is more strictly required than TM helix-destabilizing residues. Our work demonstrates that intramembrane proteases can be sequence specific and that genome-wide substrate prediction based on their recognition motifs is feasible.
广泛存在的菱形家族跨膜蛋白酶成员可切割跨膜结构域（TMD）蛋白，从而调节多种过程，如表皮生长因子受体信号转导、线粒体动力学和顶复门寄生虫的入侵。然而，由于缺乏有关其底物的信息，大多数菱形蛋白酶的生物学作用仍然不清楚。了解菱形蛋白酶如何识别其底物将阐明其机制，并且还可能允许进行底物预测。先前的工作表明，菱形蛋白酶的底物是由其 TMD 中的螺旋不稳定性决定的。在这里，我们证明菱形蛋白酶主要识别切割位点周围的特定序列。这种识别基序对于底物切割是必需的，它决定了切割位点，并且比 TM 螺旋不稳定残基更严格地要求。我们的工作表明，跨膜蛋白酶可以具有序列特异性，并且基于其识别基序进行全基因组底物预测是可行的。
