Understanding the Structure and Apo Dynamics of the Functionally Active JIP1 Fragment
Understanding the Structure and Apo Dynamics of the Functionally Active JIP1 Fragment
复制标题
了解功能活跃的 JIP1 片段的结构和 Apo 动力学
DOI：
10.1021/acs.jcim.0c01008
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发表时间：
2021
影响因子：
5.6
通讯作者：
Parish, Carol A.
中科院分区：
文献类型：
--
作者：
Ojaghlou, Neda;Airas, Justin;McRae, Lauren M.;Taylor, Cooper A.;Miller, Bill R.;Parish, Carol A.
最近的实验表明，C-Jun氨基末端激酶相互作用蛋白1（JIP 1）结合并激活c-Jun N末端激酶（JNK）蛋白。JNK是细胞凋亡的组成部分，并且该过程的失调是诸如阿尔茨海默病（AD）、肥胖和癌症的疾病的致病因素。研究还表明，JIP1可能通过促进tau蛋白和JNK之间的相互作用而增加tau的磷酸化，这也可能是AD的致病因素。关于JIP1的结构和动力学知之甚少;然而，前350个残基的氨基酸组成表明它包含一个内在无序的区域。采用分子动力学（MD）模拟方法研究了具有功能活性的JIP 1 10聚体片段的结构和动力学行为，以更好地理解该片段的溶液行为.对10个不同种子中的JIP 1 10聚体片段进行2微秒的无偏MD，总共20 μ s的模拟时间，由此，通过经典聚类鉴定出10聚体片段的7种结构稳定构象。10聚体系综也被用来建立一个马尔可夫状态模型（MSM），确定了四个亚稳态，包括六个由经典降维确定的七个构象家族。基于此MSM，四个国家之间的构象相互转换发生通过两个占主导地位的途径，每个单独的途径的概率通量为55%和44%。初始状态和最终状态之间的转换发生在平均首次通过时间为31（正向）和16（反向）μ s。
Recent experiments indicate that the C-Jun amino-terminal kinase-interacting protein 1 (JIP1) binds to and activates the c-Jun N-terminal kinase (JNK) protein. JNK is an integral part of cell apoptosis, and misregulation of this process is a causative factor in diseases such as Alzheimer’s disease (AD), obesity, and cancer. It has also been shown that JIP1 may increase the phosphorylation of tau by facilitating the interaction between the tau protein and JNK, which could also be a causative factor in AD. Very little is known about the structure and dynamics of JIP1; however, the amino acid composition of the first 350 residues suggests that it contains an intrinsically disordered region. Molecular dynamics (MD) simulations using AMBER 14 were used to study the structure and dynamics of a functionally active JIP1 10mer fragment to better understand the solution behavior of the fragment. Two microseconds of unbiased MD was performed on the JIP1 10mer fragment in 10 different seeds for a total of 20 μs of simulation time, and from this, seven structurally stable conformations of the 10mer fragment were identified via classical clustering. The 10mer ensemble was also used to build a Markov state model (MSM) that identified four metastable states that encompassed six of the seven conformational families identified by classical dimensional reduction. Based on this MSM, conformational interconversions between the four states occur via two dominant pathways with probability fluxes of 55 and 44% for each individual pathway. Transitions between the initial and final states occur with mean first passage times of 31 (forward) and 16 (reverse) μs.