A hidden Markov model for single particle tracks quantifies dynamic interactions between LFA-1 and the actin cytoskeleton.
A hidden Markov model for single particle tracks quantifies dynamic interactions between LFA-1 and the actin cytoskeleton.
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DOI：
10.1371/journal.pcbi.1000556
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发表时间：
2009-11
影响因子：
4.3
通讯作者：
Coombs D
中科院分区：
文献类型：
--
作者：
Das R;Cairo CW;Coombs D
从复杂轨迹中提取隐藏信息是单粒子和单分子实验中一直存在的问题。粒子轨迹是多种现象的结果，需要新的方法来揭示分子过程的变化。我们已经开发了一种实用的技术，能够识别实验轨迹内的多种扩散状态。我们模拟了膜相关蛋白与均匀分布的结合伙伴相互作用的单粒子轨迹，并表明，在某些简化假设下，粒子轨迹可以被视为双态隐马尔可夫模型的结果。通过模拟轨迹，我们证明了该模型可以用来识别这样一个系统的关键生物物理参数，即底层状态的扩散系数，以及它们之间的转换速率。我们使用随机优化方案来计算这些参数的最大似然估计。我们将这一分析应用于活T细胞上整合素受体淋巴细胞功能相关抗原-1 （LFA-1）的单粒子轨迹。我们的分析表明，LFA-1的扩散确实是近似双态的，其特征是细胞激活后细胞骨架相互作用的巨大变化。当靶分子与细胞表面受体蛋白结合时，许多重要的生物过程就开始了。这一事件导致一系列涉及受体和信号分子的生化反应，并最终导致细胞反应。表面受体在细胞表面是可移动的，它们的移动性受它们与细胞内蛋白相互作用的影响。我们希望了解这些相互作用的细节，以及它们如何受到细胞激活的影响。一种叫做单粒子跟踪（SPT）的实验技术使用光学显微镜来研究细胞表面受体的运动，揭示细胞膜组织的重要细节。在本文中，我们提出了一种分析SPT数据的新方法，以识别由于与细胞内蛋白质的短暂结合而降低的受体迁移率。通过我们的分析，我们能够可靠地区分当受体在膜上自由扩散时和当受体与细胞内蛋白质相互作用时的受体运动。通过观察自由态和束缚态之间跃迁的频率，我们能够估计出相互作用的反应速率。我们将我们的方法应用于T细胞中的受体LFA-1，并得出其与T细胞骨架相互作用的结论。
The extraction of hidden information from complex trajectories is a continuing problem in single-particle and single-molecule experiments. Particle trajectories are the result of multiple phenomena, and new methods for revealing changes in molecular processes are needed. We have developed a practical technique that is capable of identifying multiple states of diffusion within experimental trajectories. We model single particle tracks for a membrane-associated protein interacting with a homogeneously distributed binding partner and show that, with certain simplifying assumptions, particle trajectories can be regarded as the outcome of a two-state hidden Markov model. Using simulated trajectories, we demonstrate that this model can be used to identify the key biophysical parameters for such a system, namely the diffusion coefficients of the underlying states, and the rates of transition between them. We use a stochastic optimization scheme to compute maximum likelihood estimates of these parameters. We have applied this analysis to single-particle trajectories of the integrin receptor lymphocyte function-associated antigen-1 (LFA-1) on live T cells. Our analysis reveals that the diffusion of LFA-1 is indeed approximately two-state, and is characterized by large changes in cytoskeletal interactions upon cellular activation. Many important biological processes begin when a target molecule binds to a cell surface receptor protein. This event leads to a series of biochemical reactions involving the receptor and signalling molecules, and ultimately a cellular response. Surface receptors are mobile on the cell surface and their mobility is influenced by their interaction with intracellular proteins. We wish to understand the details of these interactions and how they are affected by cellular activation. An experimental technique called single particle tracking (SPT) uses optical microscopy to study the motion of cell-surface receptors, revealing important details about the organization of the cell membrane. In this paper, we propose a new method of analyzing SPT data to identify reduced receptor mobility as a result of transient binding to intracellular proteins. Using our analysis we are able to reliably differentiate receptor motion when a receptor is freely diffusing on the membrane versus when it is interacting with an intracellular protein. By observing the frequency of transitions between free and bound states, we are able to estimate reaction rates for the interaction. We apply our method to the receptor LFA-1 in T cells and draw conclusions about its interactions with the T cell cytoskeleton.
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影响因子：
2.9
作者：
Cairo, Christopher W.;Golan, David E.
通讯作者：
Golan, David E.
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4.8
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