Pasteurella multocida toxin activation of heterotrimeric G proteins by deamidation
Pasteurella multocida toxin activation of heterotrimeric G proteins by deamidation
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DOI：
10.1073/pnas.0900160106
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发表时间：
2009-04-28
影响因子：
11.1
通讯作者：
Aktories, Klaus
中科院分区：
文献类型：
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作者：
Orth, Joachim H. C.;Preuss, Inga;Aktories, Klaus
多杀性巴氏杆菌毒素是多杀性巴氏杆菌的主要毒力因子，能引起人和动物的巴氏杆菌病和兔、猪的萎缩性鼻炎。这种接近145 kDa的蛋白毒素通过激活G α (q)、G α (i)和G α(12/13)家族的异三聚体G蛋白来刺激各种信号转导途径，其机制尚不清楚。在这里，我们证明了多杀性巴氏杆菌毒素将G α (i2)的谷氨酰胺-205脱胺为谷氨酸。因此，毒素抑制G α (i)的内在GTPase活性，并导致G蛋白的持续激活。G α (q)也有类似的修饰，但密切相关的G α(11)则没有，因为G α不是多杀性巴氏杆菌毒素的底物。我们的数据确定了异三聚体G蛋白的α -亚基是多杀性巴氏杆菌毒素的直接分子靶标，并表明该毒素不像蛋白酶那样起作用，这是由它的硫醇蛋白酶样催化三元组提出的，而是通过脱酰胺酶活性引起G蛋白的组成性激活。
Pasteurella multocida toxin is a major virulence factor of Pasteurella multocida, which causes pasteurellosis in men and animals and atrophic rhinitis in rabbits and pigs. The approximate to 145 kDa protein toxin stimulates various signal transduction pathways by activating heterotrimeric G proteins of the G alpha(q), G alpha(i), and G alpha(12/13) families by using an as yet unknown mechanism. Here, we show that Pasteurella multocida toxin deamidates glutamine-205 of G alpha(i2) to glutamic acid. Therefore, the toxin inhibits the intrinsic GTPase activity of G alpha(i) and causes persistent activation of the G protein. A similar modification is also evident for G alpha(q), but not for the closely related G alpha(11), which is not a substrate of Pasteurella multocida toxin. Our data identify the alpha-subunits of heterotrimeric G proteins as the direct molecular target of Pasteurella multocida toxin and indicate that the toxin does not act like a protease, which was suggested from its thiol protease-like catalytic triad, but instead causes constitutive activation of G proteins by deamidase activity.