Structural Basis of Arp2/3 Complex Inhibition by GMF, Coronin, and Arpin.
Structural Basis of Arp2/3 Complex Inhibition by GMF, Coronin, and Arpin.
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DOI：
10.1016/j.jmb.2016.11.030
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发表时间：
2017-01-20
影响因子：
5.6
通讯作者：
Goode BL
中科院分区：
文献类型：
--
作者：
Sokolova OS;Chemeris A;Guo S;Alioto SL;Gandhi M;Padrick S;Pechnikova E;David V;Gautreau A;Goode BL
进化上保守的Arp2/3复合体在驱动细胞迁移、内吞和其他过程的分支肌动蛋白细丝阵列的成核过程中发挥着核心作用。为了更好地了解Arp2/3复合体的调控，我们使用单粒子电子显微镜比较了Arp2/3复合体与三种不同的抑制配体：GMF、Cortin和Arpin结合的结构。虽然这三种抑制剂在Arp2/3复合体上有不同的结合部位，但它们都诱导了一种开放的成核-非活性构象。柯罗宁促进Arp2/3复合体的标准开放构象，其N端β-螺旋体结构域位于Arp2/3复合体的p35/ARPC2亚单位附近。GMF诱导了Arp2/3复合体的两种不同的开放构象，这与GMF的两个结合位点相关。此外，GMF与柯拉宁在抑制Arp2/3复合体的肌动蛋白成核方面具有协同作用。Arpin利用VCA相关的酸性(A)基序与Arp2/3复合体相互作用，诱导了标准的开放构象，在靠近Arp2和Arp3的位置出现了两个新的团块。此外，Arpin对Arp2/3与柯罗宁和GMF的复合体具有相加的抑制作用。综上所述，这些数据表明Arp2/3复合体的构象是高度多态的，其活性可以由不同的抑制配体组合控制。
The evolutionarily conserved Arp2/3 complex plays a central role in nucleating the branched actin filament arrays that drive cell migration, endocytosis, and other processes. To better understand Arp2/3 complex regulation, we used single particle electron microscopy to compare the structures of Arp2/3 complex bound to three different inhibitory ligands: GMF, Coronin, and Arpin. Although the three inhibitors have distinct binding sites on Arp2/3 complex, they each induced an ‘open’ nucleation-inactive conformation. Coronin promoted a standard (previously described) open conformation of Arp2/3 complex, with the N-terminal β-propeller domain of Coronin positioned near the p35/ARPC2 subunit of Arp2/3 complex. GMF induced two distinct open conformations of Arp2/3 complex, which correlated with two suggested binding sites for GMF. Further, GMF synergized with Coronin in inhibiting actin nucleation by Arp2/3 complex. Arpin, which uses VCA-related acidic (A) motifs to interact with the Arp2/3 complex, induced the standard open conformation, and two new masses appeared at positions near Arp2 and Arp3. Further, Arpin showed additive inhibitory effects on Arp2/3 complex with Coronin and GMF. Together, these data suggest that Arp2/3 complex conformation is highly polymorphic and that its activities can be controlled combinatorially by different inhibitory ligands.