Depetris Rafael S, Hu Junjie, Gimpelevich Ilana, Holt Lowenna J, Daly Roger J, Hubbard Stevan R
Structural Biology Program, Skirball Institute of Biomolecular Medicine and Department of Pharmacology, New York University School of Medicine, New York, New York 10016, USA.
Mol Cell. 2005 Oct 28;20(2):325-33. doi: 10.1016/j.molcel.2005.09.001.
Grb14, a member of the Grb7 adaptor protein family, possesses a pleckstrin homology (PH) domain, a C-terminal Src homology-2 (SH2) domain, and an intervening stretch of approximately 45 residues known as the BPS region, which is unique to this adaptor family. Previous studies have demonstrated that Grb14 is a tissue-specific negative regulator of insulin receptor signaling and that inhibition is mediated by the BPS region. We have determined the crystal structure of the Grb14 BPS region in complex with the tyrosine kinase domain of the insulin receptor. The structure reveals that the N-terminal portion of the BPS region binds as a pseudosubstrate inhibitor in the substrate peptide binding groove of the kinase. Together with the crystal structure of the SH2 domain, we present a model for the interaction of Grb14 with the insulin receptor, which indicates how Grb14 functions as a selective protein inhibitor of insulin signaling.
Grb14是Grb7衔接蛋白家族的成员，具有一个普列克底物同源（PH）结构域、一个C端Src同源2（SH2）结构域，以及一段约45个残基的中间序列，称为BPS区域，这是该衔接蛋白家族所特有的。先前的研究表明，Grb14是胰岛素受体信号传导的组织特异性负调节因子，其抑制作用由BPS区域介导。我们已经确定了与胰岛素受体酪氨酸激酶结构域复合的Grb14 BPS区域的晶体结构。该结构显示，BPS区域的N端部分作为假底物抑制剂结合在激酶的底物肽结合槽中。结合SH2结构域的晶体结构，我们提出了一个Grb14与胰岛素受体相互作用的模型，该模型表明了Grb14如何作为胰岛素信号传导的选择性蛋白抑制剂发挥作用。
