Structural basis of SecA-mediated protein translocation.
Structural basis of SecA-mediated protein translocation.
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SecA 介导的蛋白质易位的结构基础
DOI：
10.1073/pnas.2208070120
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发表时间：
2023-01-10
影响因子：
11.1
通讯作者：
Li, Long
中科院分区：
文献类型：
--
作者：
Dong, Linlin;Yang, Song;Chen, Jingxia;Wu, Xiaofei;Sun, Dongjie;Song, Chen;Li, Long
细菌中绝大多数的分泌蛋白通过一种高度保守的atp酶SecA通过SecY通道在细胞膜上转运。我们报道了具有移动蛋白底物的活性SecA-SecY在ADP（二磷酸腺苷）和ATP（三磷酸腺苷）状态下的结构。这些结构揭示了SecA利用一种意想不到的机制移动蛋白质底物，这种机制与解旋酶移动DNA/RNA底物的方式惊人地相似。活跃的SecA - secy复合体和抗生素靶向的其他蛋白质易位系统具有共同的结构特征，这表明SecA可能是针对革兰氏阳性和革兰氏阴性细菌的抗生素开发的高效靶点。分泌蛋白通过原核生物中称为SecY和真核生物中称为Sec61的蛋白质传导通道在脂质膜上共翻译或翻译后易位。细菌中的绝大多数分泌蛋白在翻译后由高度保守的atp酶SecA驱动通过通道。多肽链是如何被SecA通过SecY通道移动的尚不清楚。在这里，我们报告了具有多肽底物的活性SecA-SecY易位子的电子冷冻显微镜结构。当被不同核苷酸的SecA夹住时，底物被捕获在不同的易位状态。在与ATP类似物结合后，SecA发生全局构象变化，将多肽底物推向通道，其方式与reca样解旋酶转运其核酸底物的方式相似。在共翻译易位过程中，SecA-SecY易位中多肽底物的运动与核糖体- secy复合体的运动具有相似的结构基础。
The vast majority of secretory proteins in bacteria are translocated across the cell membranes through the SecY channel by a highly conserved ATPase, SecA. We report the structures of the active SecA–SecY with a moving protein substrate in both ADP (adenosine diphosphate) and ATP (adenosine triphosphate) states. The structures reveal that SecA moves protein substrates using an unexpected mechanism that is strikingly similar to how helicases move DNA/RNA substrates. Common structural features are shared by the active SecA–SecY complex and other protein translocation systems targeted by antibiotics, suggesting that SecA could be a highly potent target for antibiotic development against both gram-positive and gram-negative bacteria. Secretory proteins are cotranslationally or posttranslationally translocated across lipid membranes via a protein-conducting channel named SecY in prokaryotes and Sec61 in eukaryotes. The vast majority of secretory proteins in bacteria are driven through the channel posttranslationally by SecA, a highly conserved ATPase. How a polypeptide chain is moved by SecA through the SecY channel is poorly understood. Here, we report electron cryomicroscopy structures of the active SecA–SecY translocon with a polypeptide substrate. The substrate is captured in different translocation states when clamped by SecA with different nucleotides. Upon binding of an ATP analog, SecA undergoes global conformational changes to push the polypeptide substrate toward the channel in a way similar to how the RecA-like helicases translocate their nucleic acid substrates. The movements of the polypeptide substrates in the SecA–SecY translocon share a similar structural basis to those in the ribosome–SecY complex during cotranslational translocation.
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