Exploration and stabilization of Ras1 mating zone: A mechanism with positive and negative feedbacks.
Exploration and stabilization of Ras1 mating zone: A mechanism with positive and negative feedbacks.
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RAS1交配区域的探索和稳定：具有正反馈和负反馈的机制。
DOI：
10.1371/journal.pcbi.1006317
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发表时间：
2018-07
影响因子：
4.3
通讯作者：
Vavylonis D
中科院分区：
文献类型：
--
作者：
Khalili B;Merlini L;Vincenzetti V;Martin SG;Vavylonis D
在交配裂变酵母细胞，传感和响应细胞外信息素浓度发生通过探索Cdc 42补丁，stochemical样品细胞皮质稳定前对交配伴侣。活性Ras 1（Ras 1-GTP），Cdc 42的上游调节因子，和Gap 1，Ras 1的GTP酶激活蛋白，定位于补丁。我们开发了一个反应扩散模型的Ras 1补丁的出现和消失的鸟嘌呤核苷酸交换因子（GEF）和Gap 1抑制的正反馈。该模型是基于新的估计Ras 1-GDP，Ras 1-GTP和Gap 1扩散系数和FRAP研究的细胞质交换率。该模型再现了探索性补丁行为和缺乏Ras 1补丁缺乏Gap 1的细胞。过渡到一个稳定的补丁可以发生的Gap 1速率常数的变化或局部增加的正反馈速率常数。该模型预测，斑块的大小和数量取决于正反馈和负反馈的强度。Ras 1补丁的大小和数量的测量过表达Ras 1 GEF或Gap 1的细胞是一致的模型。单细胞分裂酵母通过与相反交配类型的伴侣融合来交配。每一对成员都朝着它选择的伴侣生长，伴侣通过分泌的信息素发出信号。伴侣选择的过程是通过一个探索性的补丁（包含激活的信号蛋白Cdc 42和上游调节器Ras 1）发生的，该补丁在细胞皮层上组装和拆卸，在相反信息素浓度较高的区域稳定下来。我们提出了一个计算模型的分子机制驱动的动态模式的补丁探索和稳定。该模型是基于反应和扩散沿着弯曲的细胞膜，扩散系数实验测量。在该模型中，一个积极的Ras 1激活反馈回路产生一个补丁包含大部分的激活蛋白（Ras 1 GEF）。从细胞质局部募集的快速扩散抑制剂Gap 1在细胞膜上扩散，限制斑块大小并导致其衰减。Ras 1在皮层其他地方的激活自发重新启动提供了一种探索机制。过渡的系统的行为，一个单一的稳定补丁是可能的模拟信息素的检测。计算模型提供了预测补丁的数量和补丁大小依赖于我们实验测试的参数。
In mating fission yeast cells, sensing and response to extracellular pheromone concentrations occurs through an exploratory Cdc42 patch that stochastically samples the cell cortex before stabilizing towards a mating partner. Active Ras1 (Ras1-GTP), an upstream regulator of Cdc42, and Gap1, the GTPase-activating protein for Ras1, localize at the patch. We developed a reaction-diffusion model of Ras1 patch appearance and disappearance with a positive feedback by a Guanine nucleotide Exchange Factor (GEF) and Gap1 inhibition. The model is based on new estimates of Ras1-GDP, Ras1-GTP and Gap1 diffusion coefficients and rates of cytoplasmic exchange studied by FRAP. The model reproduces exploratory patch behavior and lack of Ras1 patch in cells lacking Gap1. Transition to a stable patch can occur by change of Gap1 rates constants or local increase of the positive feedback rate constants. The model predicts that the patch size and number of patches depend on the strength of positive and negative feedbacks. Measurements of Ras1 patch size and number in cells overexpressing the Ras1 GEF or Gap1 are consistent with the model. Unicellular fission yeasts mate by fusing with partners of the opposite mating type. Each pair member grows towards its selected partner that signals its presence through secreted pheromone. The process of partner selection occurs through an exploratory patch (containing activated signaling protein Cdc42 and upstream regulator Ras1) that assembles and disassembles on the cell cortex, stabilizing in regions of higher opposite pheromone concentration. We present a computational model of the molecular mechanisms driving the dynamical pattern of patch exploration and stabilization. The model is based on reaction and diffusion along the curved cell membrane, with diffusion coefficients measured experimentally. In the model, a positive Ras1 activation feedback loop generates a patch containing most of the activating protein (Ras1 GEF). The fast diffusing inhibitor Gap1 that is recruited locally from the cytoplasm spreads on the cell membrane, limiting patch size and causing its decay. Spontaneous reinitiation of Ras1 activation elsewhere on the cortex provides a mechanism for exploration. Transition of the system’s behavior to that of a single stable patch is possible upon simulated pheromone sensing. The computational model provides predictions for the number of patches and patch size dependence on parameters that we tested experimentally.
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