A molecular model for LINC complex regulation: activation of SUN2 for KASH binding.
A molecular model for LINC complex regulation: activation of SUN2 for KASH binding.
复制标题
LINC 复合体调控的分子模型：激活 SUN2 以实现 KASH 结合
DOI：
10.1091/mbc.e18-04-0266
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发表时间：
2018-08-08
影响因子：
3.3
通讯作者：
Mofrad MRK
中科院分区：
文献类型：
--
作者：
Jahed Z;Vu UT;Fadavi D;Ke H;Rathish A;Kim SCJ;Feng W;Mofrad MRK
核骨架和细胞骨架的连接物是跨越核膜（NE）的关键分子复合物，并提供核骨架和细胞骨架之间的直接连接。这些复合物的两个主要组成部分是SUN和KASH蛋白家族的成员，它们在核周空间相互作用，从而允许机械化学信号通过NE传递。哺乳动物SUN结构域蛋白SUN2的结构细节表明，SUN2必须形成一个三聚体才能与KASH结合，并且这种三聚体化是通过该蛋白的两个预测的卷曲区域CC1和CC2介导的，它们位于SUN结构域之前。最近的晶体学数据表明，CC2-SUN形成了一个意想不到的不能与KASH结合的自抑制单体。这些结构见解提出了全长SUN2如何在NE中从单体转变为三聚体的问题。在这项研究中，我们使用了一种计算方法来模拟包含CC1、CC2和SUN结构域的SUN2片段。我们使用~ 1 μs分子动力学模拟观察了这些模型结构的动力学，并表明CC1和CC2之间的相互作用可能足以使CC2- sun2从其自抑制状态中释放出来。此外，利用我们的模型和凝胶过滤分析，我们发现CC1上的E452残基参与了SUN2的单体-三聚体转变。有趣的是，在肌肉萎缩症相关的SUN2变异中发现了这种残基的突变。最后，我们提出了一个Ca2+依赖的SUN2的单体-三聚体转变。
Linkers of the nucleoskeleton and cytoskeleton are key molecular complexes that span the nuclear envelope (NE) and provide a direct linkage between the nucleoskeleton and cytoskeleton. Two major components of these complexes are members of the SUN and KASH protein families that interact in the perinuclear space to allow the transmission of mechanochemical signals across the NE. Structural details of the mammalian SUN domain protein SUN2 have established that SUN2 must form a trimer to bind to KASH, and that this trimerization is mediated through two predicted coiled-coil regions of the protein, CC1 and CC2, which precede the SUN domain. Recent crystallographic data suggest that CC2-SUN formed an unexpected autoinhibited monomer unable to bind to KASH. These structural insights raise the question of how full-length SUN2 transitions from a monomer to a trimer inside the NE. In this study we used a computational approach to model a fragment of SUN2 containing CC1, CC2, and the SUN domain. We observed the dynamics of these modeled structures using ∼1 μs molecular dynamics simulations and showed that the interplay between CC1 and CC2 may be sufficient for the release of CC2-SUN2 from its autoinhibited state. Additionally, using our models and gel filtration analysis, we show the involvement of an E452 residue on CC1 in the monomer–trimer transition of SUN2. Intriguingly, mutations in this residue have been seen in muscular dystrophy–associated SUN2 variants. Finally, we propose a Ca2+-dependent monomer–trimer transition of SUN2.