Shang Guijun, Brautigam Chad A, Chen Rui, Lu Defen, Torres-Vázquez Jesús, Zhang Xuewu
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States.
Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States.
Elife. 2017 May 24;6:e27322. doi: 10.7554/eLife.27322.
The GIPC family adaptor proteins mediate endocytosis by tethering cargo proteins to the myosin VI motor. The structural mechanisms for the GIPC/cargo and GIPC/myosin VI interactions remained unclear. PlexinD1, a transmembrane receptor that regulates neuronal and cardiovascular development, is a cargo of GIPCs. GIPC-mediated endocytic trafficking regulates PlexinD1 signaling. Here, we unravel the mechanisms of the interactions among PlexinD1, GIPCs and myosin VI by a series of crystal structures of these proteins in apo or bound states. GIPC1 forms a domain-swapped dimer in an autoinhibited conformation that hinders binding of both PlexinD1 and myosin VI. PlexinD1 binding to GIPC1 releases the autoinhibition, promoting its interaction with myosin VI. GIPCs and myosin VI interact through two distinct interfaces and form an open-ended alternating array. Our data support that this alternating array underlies the oligomerization of the GIPC/Myosin VI complexes in solution and cells.
GIPC家族衔接蛋白通过将货物蛋白拴系到肌球蛋白VI马达上来介导内吞作用。GIPC与货物蛋白以及GIPC与肌球蛋白VI相互作用的结构机制仍不清楚。PlexinD1是一种调节神经元和心血管发育的跨膜受体，是GIPC的货物蛋白。GIPC介导的内吞运输调节PlexinD1信号传导。在这里，我们通过这些蛋白质在无配体或结合状态下的一系列晶体结构，揭示了PlexinD1、GIPC和肌球蛋白VI之间相互作用的机制。GIPC1以自抑制构象形成结构域交换二聚体，阻碍PlexinD1和肌球蛋白VI的结合。PlexinD1与GIPC1的结合解除了自抑制，促进其与肌球蛋白VI的相互作用。GIPC和肌球蛋白VI通过两个不同的界面相互作用，并形成一个开放式交替阵列。我们的数据支持这种交替阵列是溶液和细胞中GIPC/肌球蛋白VI复合物寡聚化的基础。
