Force transduction creates long-ranged coupling in ribosomes stalled by arrest peptides
Force transduction creates long-ranged coupling in ribosomes stalled by arrest peptides
复制标题
力转导在被阻滞肽阻止的核糖体中产生长程耦合
DOI：
10.1101/2020.10.16.342899
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Thomas F. Miller
中科院分区：
文献类型：
--
作者：
M. Zimmer;Michiel J. M. Niesen;Thomas F. Miller
力敏感的阻滞肽通过阻止核糖体的翻译来调节蛋白质的生物合成。当新生的阻滞肽受到足够大的拉力以打破失速时，合成就可以恢复。有效的拖延取决于大量氨基酸的特异性，包括距离肽基转移酶中心(PTC)几十埃的氨基酸。目前，这些远离PTC的必需氨基酸的作用以及力诱导重新启动的机制尚不清楚。我们使用上百条跨越120μS的独立分子动力学轨迹，结合动力学分析来表征阻止肽SECM在力诱导重启途径上的障碍。我们发现远离PTC的必需氨基酸在控制外力传递方面起着主要作用。在沿着失速打破途径的连续状态下，所施加的力沿着新生链向上传播，直到到达SECM和PTC的C末端，导致构象变化，从而允许重新开始翻译。在VemP失速打破途径中也观察到了类似的力通过多个状态传播的机制，但VemP中的二级结构允许通过中间态的转变顺序的异质性。这两个阻滞肽的结果都解释了距离核糖体催化中心数十埃的残基如何通过调节对外力的反应和屏蔽负责维持PTC停滞状态的氨基酸来影响停滞效率。意义陈述由于新生蛋白质是由核糖体合成的，它们与环境的相互作用可以对新生蛋白质产生拉力，并将其传递到核糖体的催化中心。这些力量会影响翻译的速度，甚至影响翻译的结果。我们使用模拟来刻画沿着阻止肽的力传导路径，并发现新生蛋白质中的二级结构及其与核糖体出口隧道的相互作用如何阻碍力传播。这解释了距离核糖体催化中心几十埃的阻滞肽中的氨基酸是如何导致停滞的，更广泛地说，这表明新生蛋白质的结构特征决定了核糖体对环境做出功能性反应的能力。
Force-sensitive arrest peptides regulate protein biosynthesis by stalling the ribosome as they are translated. Synthesis can be resumed when the nascent arrest peptide experiences a pulling force of sufficient magnitude to break the stall. Efficient stalling is dependent on the specific identity of a large number of amino acids, including amino acids which are tens of angstroms away from the peptidyl transferase center (PTC). The mechanism of force-induced restart and the role of these essential amino acids far from the PTC is currently unknown. We use hundreds of independent molecular dynamics trajectories spanning over 120 μs in combination with kinetic analysis to characterize the barriers along the force-induced restarting pathway for the arrest peptide SecM. We find that the essential amino acids far from the PTC play a major role in controlling the transduction of applied force. In successive states along the stall-breaking pathway, the applied force propagates up the nascent chain until it reaches the C-terminus of SecM and the PTC, inducing conformational changes that allow for restart of translation. A similar mechanism of force propagation through multiple states is observed in the VemP stall-breaking pathway, but secondary structure in VemP allows for heterogeneity in the order of transitions through intermediate states. Results from both arrest peptides explain how residues that are tens of angstroms away from the catalytic center of the ribosome impact stalling efficiency by mediating the response to an applied force and shielding the amino acids responsible for maintaining the stalled state of the PTC. Significance Statement As nascent proteins are synthesized by the ribosome, their interactions with the environment can create pulling forces on the nascent protein that can be transmitted to the ribosome’s catalytic center. These forces can affect the rate and even the outcome of translation. We use simulations to characterize the pathway of force transduction along arrest peptides and discover how secondary structure in the nascent protein and its interactions with the ribosome exit tunnel impede force propagation. This explains how amino acids in arrest peptides that are tens of angstroms away from the ribosome’s catalytic center contribute to stalling, and, more broadly, suggests how structural features in the nascent protein dictate the ribosome’s ability to functionally respond to its environment.
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影响因子：
16.6
作者：
Bullerjahn, Jakob T.;Sturm, Sebastian;Kroy, Klaus
通讯作者：
Kroy, Klaus
DOI：
10.1126/science.1177662
发表时间：
2009-12-04
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Seidelt B;Innis CA;Wilson DN;Gartmann M;Armache JP;Villa E;Trabuco LG;Becker T;Mielke T;Schulten K;Steitz TA;Beckmann R
通讯作者：
Beckmann R
DOI：
10.1073/pnas.1810523115
发表时间：
2018-11-27
影响因子：
11.1
作者：
Tian P;Steward A;Kudva R;Su T;Shilling PJ;Nickson AA;Hollins JJ;Beckmann R;von Heijne G;Clarke J;Best RB
通讯作者：
Best RB
影响因子：
12.4
作者：
Woodside MT;Block SM
通讯作者：
Block SM
影响因子：
6.8
作者：
Wilson, Daniel N.;Arenz, Stefan;Beckmann, Roland
通讯作者：
Beckmann, Roland