Eron Scott J, Raghupathi Kishore, Hardy Jeanne A
Department of Chemistry, University of Massachusetts Amherst, 104 LGRT, 710 North Pleasant Street, Amherst, MA 01003, USA.
Department of Chemistry, University of Massachusetts Amherst, 104 LGRT, 710 North Pleasant Street, Amherst, MA 01003, USA.
Structure. 2017 Jan 3;25(1):27-39. doi: 10.1016/j.str.2016.11.001. Epub 2016 Nov 23.
Caspases, the cysteine proteases that execute apoptosis, are tightly regulated via phosphorylation by a series of kinases. Although all apoptotic caspases work in concert to promote apoptosis, different kinases regulate individual caspases. Several sites of caspase-7 phosphorylation have been reported, but without knowing the molecular details, it has been impossible to exploit or control these complex interactions, which normally prevent unwanted proliferation. During dysregulation, PAK2 kinase plays an alternative anti-apoptotic role, phosphorylating caspase-7 and promoting unfettered cell growth and chemotherapeutic resistance. PAK2 phosphorylates caspase-7 at two sites, inhibiting activity using two different molecular mechanisms, before and during apoptosis. Phosphorylation of caspase-7 S30 allosterically obstructs its interaction with caspase-9, preventing intersubunit linker processing, slowing or preventing caspase-7 activation. S239 phosphorylation renders active caspase-7 incapable of binding substrate, blocking later events in apoptosis. Each of these mechanisms is novel, representing new opportunities for synergistic control of caspases and their counterpart kinases.
半胱天冬酶是执行细胞凋亡的半胱氨酸蛋白酶，通过一系列激酶的磷酸化作用受到严格调控。尽管所有凋亡性半胱天冬酶协同作用以促进细胞凋亡，但不同的激酶调控单个半胱天冬酶。已有报道称半胱天冬酶 -7 有多个磷酸化位点，但由于不清楚分子细节，一直无法利用或控制这些通常可防止不必要增殖的复杂相互作用。在调节异常期间，PAK2 激酶发挥另一种抗凋亡作用，磷酸化半胱天冬酶 -7 并促进不受限制的细胞生长和化疗耐药性。PAK2 在两个位点磷酸化半胱天冬酶 -7，在细胞凋亡之前和期间使用两种不同的分子机制抑制其活性。半胱天冬酶 -7 的 S30 磷酸化通过变构作用阻碍其与半胱天冬酶 -9 的相互作用，阻止亚基间连接区的加工，减缓或阻止半胱天冬酶 -7 的激活。S239 磷酸化使活性半胱天冬酶 -7 无法结合底物，阻断细胞凋亡后期事件。这些机制中的每一种都是新颖的，为协同控制半胱天冬酶及其对应激酶提供了新的机会。
