Structure and function of the virulence-associated high-temperature requirement a of mycobacterium tuberculosis
Structure and function of the virulence-associated high-temperature requirement a of mycobacterium tuberculosis
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DOI：
10.1021/bi701929m
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发表时间：
2008-06-10
期刊：
影响因子：
2.9
通讯作者：
Sacchettini, James C.
中科院分区：
文献类型：
--
作者：
MohamedMohaideen, Nilofar N.;Palaninathan, Satheesh K.;Sacchettini, James C.
高温需要A（HtrA）丝氨酸蛋白酶家族在大肠杆菌的环境和细胞应激损伤控制系统中发挥重要作用。结核分枝杆菌（Mycobacterium tuberculosis，Mtb）具有三种推定的HtrA样蛋白酶，HtrA1、HtrA2和HtrA3。htrA2的缺失在TB的小鼠模型中产生减弱的毒力。生化分析表明，HtrA2可以作为蛋白酶和伴侣蛋白。在2.0埃分辨率下测定的HtrA2的三维结构显示，蛋白酶结构域形成三聚体的中心核心，PDZ结构域延伸到外围。与E.在大肠杆菌DegS和DegP中，由于形成丝氨酸蛋白酶样催化三联体及其独特设计的氧阴离子孔，该蛋白酶是天然活性的。每个HtrA2分子的蛋白酶和PDZ结合口袋都被自身蛋白水解肽产物占据，并揭示了一种新的自我调节机制的线索，该机制可能在HtrA相关的Mtb毒力中具有重要意义。
The high-temperature requirement A (HtrA) family of serine proteases has been shown to play an important role in the environmental and cellular stress damage control system in Escherichia coli. Mycobacterium tuberculosis (Mtb) has three putative HtrA-like proteases, HtrA1, HtrA2, and HtrA3. The deletion of htrA2 gives attenuated virulence in a mouse model of TB. Biochemical analysis reveals that HtrA2 can function both as a protease and as a chaperone. The three-dimensional structure of HtrA2 determined at 2.0 angstrom resolution shows that the protease domains form the central core of the trimer and the PDZ domains extend to the periphery. Unlike E. coli DegS and DegP, the protease is naturally active due to the formation of the serine protease-like catalytic triad and its uniquely designed oxyanion hole. Both protease and PDZ binding pockets of each HtrA2 molecule are occupied by autoproteolytic peptide products and reveal clues for a novel autoregulatory mechanism that might have significant importance in HtrA-associated virulence of Mtb.