Force-induced unfolding simulations of the human Notch1 negative regulatory region: possible roles of the heterodimerization domain in mechanosensing.
Force-induced unfolding simulations of the human Notch1 negative regulatory region: possible roles of the heterodimerization domain in mechanosensing.
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DOI：
10.1371/journal.pone.0022837
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Zolkiewska A
中科院分区：
文献类型：
--
作者：
Chen J;Zolkiewska A
Notch受体是Notch信号通路的核心组成部分，在发育过程中的细胞命运决定以及组织稳态中发挥核心作用。在配体结合后，Notch在S2位点被ADAM蛋白酶依次切割，在S3位点被γ-分泌酶复合物依次切割。Notch受体负调控区（NRR）的最新X射线结构揭示了一个自抑制折叠，其中NRR的三个保护性Lin 12/Notch重复序列（LNR）屏蔽了异源二聚化（HD）结构域中的S2切割位点。解释配体结合如何驱动NRR构象从蛋白酶抗性状态到蛋白酶敏感状态的模型之一调用了在配体内吞作用后施加在NRR上的机械力。在这里，我们结合了基于物理的原子模拟和基于拓扑的粗粒度建模来研究人类Notch 1 NRR的内在和力诱导的折叠和展开机制。模拟支持施加到NRR末端的外力以明确定义的、很大程度上连续的方式使LNR模块从异源二聚化（HD）结构域脱离。重要的是，机械力可以以功能相关的方式进一步驱动HD结构域的局部解折叠，这将在异源二聚体解离之前提供对S2位点的完全蛋白水解。我们进一步分析了HD结构域的局部结构特征、内禀折叠自由能表面和相关运动。结果是一致的模型，其中HD域具有固有的机械传感特性，可以利用在Notch激活。HD结构域在配体依赖性Notch激活中的这种潜在作用可能对理解正常和异常Notch信号传导具有意义。
Notch receptors are core components of the Notch signaling pathway and play a central role in cell fate decisions during development as well as tissue homeostasis. Upon ligand binding, Notch is sequentially cleaved at the S2 site by an ADAM protease and at the S3 site by the γ-secretase complex. Recent X-ray structures of the negative regulatory region (NRR) of the Notch receptor reveal an auto-inhibited fold where three protective Lin12/Notch repeats (LNR) of the NRR shield the S2 cleavage site housed in the heterodimerization (HD) domain. One of the models explaining how ligand binding drives the NRR conformation from a protease-resistant state to a protease-sensitive one invokes a mechanical force exerted on the NRR upon ligand endocytosis. Here, we combined physics-based atomistic simulations and topology-based coarse-grained modeling to investigate the intrinsic and force-induced folding and unfolding mechanisms of the human Notch1 NRR. The simulations support that external force applied to the termini of the NRR disengages the LNR modules from the heterodimerization (HD) domain in a well-defined, largely sequential manner. Importantly, the mechanical force can further drive local unfolding of the HD domain in a functionally relevant fashion that would provide full proteolytic access to the S2 site prior to heterodimer disassociation. We further analyzed local structural features, intrinsic folding free energy surfaces, and correlated motions of the HD domain. The results are consistent with a model in which the HD domain possesses inherent mechanosensing characteristics that could be utilized during Notch activation. This potential role of the HD domain in ligand-dependent Notch activation may have implications for understanding normal and aberrant Notch signaling.
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