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首页> 外文期刊>Journal of Molecular Biology >Structures of dimeric GIT1 and trimeric beta-PIX and implications for GIT-PIX complex assembly.
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Structures of dimeric GIT1 and trimeric beta-PIX and implications for GIT-PIX complex assembly.

机译：二聚体GIT1和三聚体β-PIX的结构及其对GIT-PIX复杂装配的影响。

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摘要

GIT (G protein-coupled receptor kinase-interacting protein) and PIX (p21-activated kinase-interacting exchange factor) family proteins integrate signaling pathways involving Arf and Rho family GTPases. GIT1 and beta-PIX form a constitutively associated complex that acts as a scaffold to allow the formation of large multiprotein assemblies that regulate synaptogenesis, cell polarity and cell migration among other physiological processes. Complex formation is mediated by the GIT binding domain (GBD) in beta-PIX, which recognizes the Spa homology domain of GIT1. Both binding domains are adjacent to predicted coiled-coil segments that allow homo-oligomerization of GIT1 and beta-PIX, respectively. Oligomerization of GIT and PIX proteins is important for their physiological functions, and deletion of the coiled-coil domains interferes with correct subcellular localization and the GEF (guanine nucleotide exchange factor) activity of PIX. We have solved the crystal structures of the CC domains of GIT1 and beta-PIX and determined the stoichiometry of complex formation between the two proteins in order to understand the molecular architecture of the GIT1-beta-PIX complex. The crystal structure of the CC domain of GIT1 solved at 1.4 A resolution shows a dimeric, parallel CC that spans 67 A in length. Unexpectedly, and in contrast to prevalent dimeric models, the structure of the CC region of beta-PIX determined at 2.8 A resolution, combined with hydrodynamic studies, reveals that this protein forms a parallel trimer. Furthermore, we demonstrate that dimeric GIT and trimeric PIX form an unusual high-affinity heteropentameric complex in which each Spa homology domain of the GIT1 dimer recognizes one GBD of the beta-PIX trimer, leaving one GBD unoccupied. These results can serve as a basis to better understand oligomerization-dependent GIT1-beta-PIX-regulated signaling events and provide an insight into the architecture of large signaling complexes involving GIT1 and beta-PIX.
机译：GIT（G蛋白偶联受体激酶相互作用蛋白）和PIX（p21活化激酶相互作用交换因子）家族蛋白整合了涉及Arf和Rho家族GTPases的信号通路。 GIT1和β-PIX构成一个组成上相关的复合物，该复合物充当支架以允许形成大的多蛋白装配体，该装配体在其他生理过程中调节突触发生，细胞极性和细胞迁移。复合物的形成是由beta-PIX中的GIT结合域（GBD）介导的，该区域识别GIT1的Spa同源域。两个结合结构域均与预测的卷曲螺旋片段相邻，后者分别允许GIT1和β-PIX进行均聚。 GIT和PIX蛋白的寡聚化对其生理功能很重要，而卷曲螺旋结构域的缺失会干扰PIX的正确亚细胞定位和GEF（鸟嘌呤核苷酸交换因子）活性。我们已经解决了GIT1和β-PIX的CC域的晶体结构，并确定了两种蛋白质之间形成复合物的化学计量，以了解GIT1-β-PIX复合物的分子结构。以1.4 A分辨率解析的GIT1 CC域的晶体结构显示出二聚体平行CC，其长度跨度为67A。出乎意料的是，与流行的二聚体模型相反，以2.8 A分辨率确定的β-PIXCC区的结构与流体动力学研究相结合，揭示了该蛋白形成了平行三聚体。此外，我们证明了二聚体GIT和三聚体PIX形成了一种不同寻常的高亲和力异五聚体复合物，其中GIT1二聚体的每个Spa同源域都识别一个β-PIX三聚体的GBD，而一个GBD未被占用。这些结果可作为基础，以更好地理解寡聚化依赖性的GIT1-β-PIX调节的信号事件，并为深入了解涉及GIT1和β-PIX的大型信号复合物的体系结构提供依据。

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