Dimerization in the Grb7 protein.
Dimerization in the Grb7 protein.
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DOI：
10.1002/jmr.2205
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发表时间：
2012-08
影响因子：
2.7
通讯作者：
Lyons, Barbara A.
中科院分区：
文献类型：
--
作者：
Peterson, Tabitha A.;Benallie, Renee L.;Bradford, Andrew M.;Pias, Sally C.;Yazzie, Jaron;Lor, Siamee N.;Haulsee, Zachary M.;Park, Chad K.;Johnson, Dennis L.;Rohrschneider, Larry R.;Spuches, Anne;Lyons, Barbara A.
在之前的研究中，我们发现生长因子受体结合蛋白 7 (Grb7) 的酪氨酸磷酸化状态会影响其与转录调节因子 FHL2 和皮质素相互作用蛋白（人 HS-1 相关蛋白-1）结合的能力。在这里，我们提出的结果描述了 Grb7-Src 同源 2 (SH2) 结构域中二聚化在其结构完整性和结合磷酸化酪氨酸肽配体的能力方面的重要性。酪氨酸磷酸化模拟突变体 (Y80E–Grb7–SH2) 在很大程度上二聚化缺陷，并结合代表受体酪氨酸激酶 (RTK) erbB2 的酪氨酸磷酸化肽，其热力学特征与野生型 SH2 结构域不同。另一种二聚化缺陷突变体 (F99R–Grb7–SH2) 结合磷酸化的 erbB2 肽，具有类似的热力学特征变化。 Y80E–Grb7–SH2 和 F99R–Grb7–SH2 均通过圆二色性测量构建，但通过圆二色性和核磁共振测量，相对于野生型–Grb7–SH2 结构域，显示出热稳定性降低。众所周知，RTK 的二聚化状态（作为 Grb7 等衔接蛋白的结合伴侣）在其调节中发挥着重要作用。在这里，我们提出Grb7-SH2结构域酪氨酸残基的磷酸化状态可以控制Grb7二聚化，并且二聚化可能是Grb7与RTK（例如erbB2）结合的重要调节步骤。通过这种方式，额外的二聚化依赖性调节可能发生在 RTK 介导的信号通路中膜结合激酶的下游。
In previous studies, we showed that the tyrosine phosphorylation state of growth factor receptor–bound protein 7 (Grb7) affects its ability to bind to the transcription regulator FHL2 and the cortactin-interacting protein, human HS-1-associated protein-1. Here, we present results describing the importance of dimerization in the Grb7–Src homology 2 (SH2) domain in terms of its structural integrity and the ability to bind phosphorylated tyrosine peptide ligands. A tyrosine phosphorylation-mimic mutant (Y80E–Grb7–SH2) is largely dimerization deficient and binds a tyrosine-phosphorylated peptide representative of the receptor tyrosine kinase (RTK) erbB2 with differing thermodynamic characteristics than the wild-type SH2 domain. Another dimerization-deficient mutant (F99R–Grb7–SH2) binds the phosphorylated erbB2 peptide with similarly changed thermodynamic characteristics. Both Y80E–Grb7–SH2 and F99R–Grb7–SH2 are structured by circular dichroism measurements but show reduced thermal stability relative to the wild type–Grb7–SH2 domain as measured by circular dichroism and nuclear magnetic resonance. It is well known that the dimerization state of RTKs (as binding partners to adaptor proteins such as Grb7) plays an important role in their regulation. Here, we propose the phosphorylation state of Grb7–SH2 domain tyrosine residues could control Grb7 dimerization, and dimerization may be an important regulatory step in Grb7 binding to RTKs such as erbB2. In this manner, additional dimerization-dependent regulation could occur downstream of the membrane-bound kinase in RTK-mediated signaling pathways.
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