1] Institute of Molecular Biology, University of Oregon, Eugene, Oregon, USA. [2] Department of Chemistry and Biochemistry, University of Oregon, Eugene, Oregon, USA.
Nat Struct Mol Biol. 2013 Sep;20(9):1062-8. doi: 10.1038/nsmb.2628. Epub 2013 Jul 28.
The Arp2/3 complex mediates formation of complex cellular structures such as lamellipodia by nucleating branched actin filaments. Arp2/3-complex activity is precisely controlled by over a dozen regulators, yet the structural mechanism by which regulators interact with the complex is unknown. GMF is a recently discovered regulator of the Arp2/3 complex that can inhibit nucleation and disassemble branches. We solved the structure of the 240-kDa assembly of Mus musculus GMF and Bos taurus Arp2/3 complex and found that GMF binds the barbed end of Arp2, overlapping with the proposed binding site of WASP-family proteins. The structure suggests that GMF can bind branch junctions in the manner that cofilin binds filament sides, consistent with a modified cofilin-like mechanism for debranching by GMF. The GMF-Arp2 interface reveals how the ADF-H actin-binding domain in GMF is exploited to specifically recognize Arp2/3 complex and not actin.
Arp2/3 复合物通过成核分支肌动蛋白丝来介导细胞片状伪足等复杂细胞结构的形成。Arp2/3 复合物的活性受到超过十几个调节因子的精确控制，但调节因子与复合物相互作用的结构机制尚不清楚。GMF 是最近发现的 Arp2/3 复合物的调节剂，它可以抑制成核和分支解体。我们解析了肌球蛋白鼠 GMF 和牛 Arp2/3 复合物 240kDa 组装体的结构，发现 GMF 结合 Arp2 的暴露出的末端，与 WASP 家族蛋白的假定结合位点重叠。该结构表明 GMF 可以结合分支连接处，类似于肌动蛋白结合丝侧面的结合方式，这与 GMF 通过解分支的改良肌动蛋白类似机制一致。GMF-Arp2 界面揭示了 GMF 中的 ADF-H 肌动蛋白结合结构域如何被利用来特异性识别 Arp2/3 复合物而不是肌动蛋白。
