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纺锤体组装检查点信号级联的异位激活揭示了其生化设计。

Ectopic Activation of the Spindle Assembly Checkpoint Signaling Cascade Reveals Its Biochemical Design.

机构信息

Department of Biophysics, University of Michigan, Ann Arbor, MI 48109, USA.

Whitehead Institute for Biomedical Research and Department of Biology, MIT, Nine Cambridge Center, Cambridge, MA 02142, USA.

出版信息

Curr Biol. 2019 Jan 7;29(1):104-119.e10. doi: 10.1016/j.cub.2018.11.054. Epub 2018 Dec 27.

Abstract

Switch-like activation of the spindle assembly checkpoint (SAC) is critical for accurate chromosome segregation and for cell division in a timely manner. To determine the mechanisms that achieve this, we engineered an ectopic, kinetochore-independent SAC activator: the "eSAC." The eSAC stimulates SAC signaling by artificially dimerizing Mps1 kinase domain and a cytosolic KNL1 phosphodomain, the kinetochore signaling scaffold. By exploiting variable eSAC expression in a cell population, we defined the dependence of the eSAC-induced mitotic delay on eSAC concentration in a cell to reveal the dose-response behavior of the core signaling cascade of the SAC. These quantitative analyses and subsequent mathematical modeling of the dose-response data uncover two crucial properties of the core SAC signaling cascade: (1) a cellular limit on the maximum anaphase-inhibitory signal that the cascade can generate due to the limited supply of SAC proteins and (2) the ability of the KNL1 phosphodomain to produce the anaphase-inhibitory signal synergistically, when it recruits multiple SAC proteins simultaneously. We propose that these properties together achieve inverse, non-linear scaling between the signal output per kinetochore and the number of signaling kinetochores. When the number of kinetochores is low, synergistic signaling by KNL1 enables each kinetochore to produce a disproportionately strong signal output. However, when many kinetochores signal concurrently, they compete for a limited supply of SAC proteins. This frustrates synergistic signaling and lowers their signal output. Thus, the signaling activity of unattached kinetochores will adapt to the changing number of signaling kinetochores to enable the SAC to approximate switch-like behavior.

摘要

纺锤体组装检查点(SAC)的开关样激活对于准确的染色体分离和及时的细胞分裂至关重要。为了确定实现这一目标的机制,我们设计了一种异位的、动粒独立的 SAC 激活剂:“eSAC”。eSAC 通过人工二聚化 Mps1 激酶结构域和细胞质 KNL1 磷酸结构域(动粒信号支架)来刺激 SAC 信号。通过在细胞群体中利用可变的 eSAC 表达,我们定义了 eSAC 诱导的有丝分裂延迟对细胞中 eSAC 浓度的依赖性,从而揭示了 SAC 核心信号级联的剂量反应行为。这些定量分析和随后对剂量反应数据的数学建模揭示了核心 SAC 信号级联的两个关键特性:(1)由于 SAC 蛋白的有限供应,级联可以产生的后期抑制信号的细胞极限;(2)当 KNL1 磷酸结构域同时招募多个 SAC 蛋白时,它产生后期抑制信号的协同能力。我们提出,这些特性共同实现了每个动粒的信号输出与信号动粒数量之间的反向、非线性缩放。当动粒数量较低时,KNL1 的协同信号使每个动粒产生不成比例的强信号输出。然而,当许多动粒同时发出信号时,它们会争夺有限的 SAC 蛋白供应。这挫败了协同信号并降低了它们的信号输出。因此,未连接的动粒的信号活性将适应信号动粒数量的变化,以使 SAC 能够近似开关样行为。

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