Xiang Song, Kim Eun Young, Connelly Jessica J, Nassar Nicolas, Kirsch Joachim, Winking Jan, Schwarz Günter, Schindelin Hermann
Department of Biochemistry, SUNY Stony Brook, NY 11794-5215, USA.
J Mol Biol. 2006 May 26;359(1):35-46. doi: 10.1016/j.jmb.2006.03.019. Epub 2006 Mar 29.
The synaptic localization of ion channel receptors is essential for efficient synaptic transmission and the precise regulation of diverse neuronal functions. In the central nervous system, ion channel receptors reside in the postsynaptic membrane where they are juxtaposed to presynaptic terminals. For proper function, these ion channels have to be anchored to the cytoskeleton, and in the case of the inhibitory glycine and gamma-amino-butyric acid type A (GABA(A)) receptors this interaction is mediated by a gephyrin centered scaffold. Highlighting its central role in this receptor anchoring scaffold, gephyrin interacts with a number of proteins, including the neurospecific guanine nucleotide exchange factor collybistin. Collybistin belongs to the Dbl family of guanine nucleotide exchange factors, occurs in multiple splice variants, and is specific for Cdc42, a small GTPase belonging to the Rho family. The 2.3 Angstroms resolution crystal structure of the Cdc42-collybistin II complex reveals a novel conformation of the switch I region of Cdc42. It also provides the first direct observation of structural changes in the relative orientation of the Dbl-homology domain and the pleckstrin-homology domain in the same Dbl family protein. Biochemical data indicate that gephyrin negatively regulates collybistin activity.
离子通道受体的突触定位对于高效的突触传递和各种神经元功能的精确调节至关重要。在中枢神经系统中，离子通道受体位于突触后膜，与突触前终末相邻。为了正常发挥功能，这些离子通道必须锚定在细胞骨架上，对于抑制性甘氨酸和γ-氨基丁酸A型（GABA(A)）受体而言，这种相互作用由一个以桥连蛋白为中心的支架介导。桥连蛋白在这种受体锚定支架中发挥核心作用，它与许多蛋白质相互作用，包括神经特异性鸟嘌呤核苷酸交换因子结肠直肠癌缺失蛋白。结肠直肠癌缺失蛋白属于鸟嘌呤核苷酸交换因子的Dbl家族，有多种剪接变体，并且对Cdc42具有特异性，Cdc42是一种属于Rho家族的小GTP酶。Cdc42-结肠直肠癌缺失蛋白II复合物的2.3埃分辨率晶体结构揭示了Cdc42开关I区域的一种新构象。它还首次直接观察到同一Dbl家族蛋白中Dbl同源结构域和普列克底物蛋白同源结构域相对取向的结构变化。生化数据表明桥连蛋白对结肠直肠癌缺失蛋白的活性具有负调节作用。
