Urban Siniša, Moin Syed M
Howard Hughes Medical Institute, Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Howard Hughes Medical Institute, Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Cell Rep. 2014 Sep 11;8(5):1241-7. doi: 10.1016/j.celrep.2014.07.039. Epub 2014 Aug 21.
Rhomboid proteases are integral membrane enzymes that regulate cell signaling, adhesion, and organelle homeostasis pathways, making substrate specificity a key feature of their function. Interestingly, we found that perturbing the membrane pharmacologically in living cells had little effect on substrate processing but induced inappropriate cleavage of nonsubstrates by rhomboid proteases. A subclass of drugs known to modulate γ-secretase activity acted on the membrane directly and induced nonsubstrate cleavage by rhomboid proteases but left true substrate cleavage sites unaltered. These observations highlight an active role for the membrane in guiding rhomboid selectivity and caution that membrane-targeted drugs should be evaluated for cross-activity against membrane-resident enzymes that are otherwise unrelated to the intended drug target. Furthermore, some γ-secretase-modulating activity or toxicity could partly result from global membrane effects.
菱形蛋白酶是整合膜酶，可调节细胞信号传导、黏附及细胞器稳态途径，因此底物特异性是其功能的关键特征。有趣的是，我们发现，在活细胞中通过药理学方法干扰膜对底物加工影响不大，但会诱导菱形蛋白酶对非底物进行不适当的切割。一类已知可调节γ-分泌酶活性的药物直接作用于膜，并诱导菱形蛋白酶对非底物进行切割，但真正的底物切割位点未改变。这些观察结果凸显了膜在引导菱形蛋白酶选择性方面的积极作用，并提醒人们应评估针对膜的药物对其他与预期药物靶点无关的膜驻留酶的交叉活性。此外，一些γ-分泌酶调节活性或毒性可能部分源于整体膜效应。
