Ratcheting in post-translational protein translocation: A mathematical model
Ratcheting in post-translational protein translocation: A mathematical model
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DOI：
10.1006/jmbi.2000.4302
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发表时间：
2001-01-19
影响因子：
5.6
通讯作者：
Heinrich, R
中科院分区：
文献类型：
--
作者：
Liebermeister, W;Rapoport, TA;Heinrich, R
我们已经开发了一个非稳态数学模型描述翻译后蛋白质易位跨内质网膜。多肽链通过内质网膜中的通道的运动被认为是随机过程，其通过BiP（Kar 2 p）（ATP酶的Hsp 70家族的成员）的结合而偏向于通道的内腔侧（棘轮模型）。假设链通过通道的运动是由被动扩散（布朗棘轮）引起的，该模型描述了所有可用的实验数据。模型参数的最佳设置表明，棘轮机制的功能在接近最大速率，是相对不敏感的变化的关联或解离速率常数的BiP或其浓度。多肽在通道内扩散的估计速率常数表明该链与通道壁接触。由于拟合模型的数据需要向后的速率常数大于前向常数在早期的扩散步骤，易位必须发生对抗力。后者可以例如由多肽链在胞质溶胶中的解折叠产生。我们的研究结果表明，棘轮可以转运多肽对自由能约25 kJ/mol，没有显着的阻滞易位。该模型还表明，BiP棘轮是优化的，允许快速易位与最小消耗的ATP和快速解离的BiP在ER的管腔中耦合。最后，我们已经估计了最大的疏水性的多肽片段，从通道到脂质相的横向分区不会导致显着的阻滞易位。(C)北京：科学出版社.
We have developed a non-steady-state mathematical model describing post-translational protein translocation across the endoplasmic reticulum membrane. Movement of the polypeptide chain through the channel in the endoplasmic reticulum membrane is considered to be a stochastic process which is biased at the lumenal side of the channel by the binding of BiP (Kar2p), a member of the Hsp70 family of ATPases (ratcheting model). Assuming that movement of the chain through the channel is caused by passive diffusion (Brownian ratchet), the model describes all available experimental data. The optimum set of model parameters indicates that the ratcheting mechanism functions at near-maximum rate, being relatively insensitive to variations of the association or dissociation rate constants of BiP or its concentration. The estimated rate constant for diffusion of a polypeptide inside the channel indicates that the chain makes contact with the walls of the channel. Since fitting of the model to the data required that the backward rate constant be larger than the forward constant during early diffusion steps, translocation must occur against a force. The latter may arise, for example, from the unfolding of the polypeptide chain in the cytosol. Our results indicate that the ratchet can transport polypeptides against a free energy of about 25 kJ/mol without significant retardation of translocation. The modeling also suggests that the BiP ratchet is optimized, allowing fast translocation to be coupled with minimum consumption of ATP and rapid dissociation of BiP in the lumen of the ER. Finally, we have estimated the maximum hydrophobicity of a polypeptide segment up to which lateral partitioning from the channel into the lipid phase does not result in significant retardation of translocation. (C) 2001 Academic Press.