The Intertwining of Structure and Function: Proposed Helix-Swapping of the SH2 Domain of Grb7, A Regulatory Protein Implicated in Cancer Progression and Inflammation
The Intertwining of Structure and Function: Proposed Helix-Swapping of the SH2 Domain of Grb7, A Regulatory Protein Implicated in Cancer Progression and Inflammation
复制标题
DOI：
10.1615/critrevimmunol.v30.i3.70
复制
发表时间：
2010-01-01
影响因子：
1.3
通讯作者：
Lyons, Barbara A.
中科院分区：
文献类型：
--
作者：
Pias, Sally C.;Peterson, Tabitha A.;Lyons, Barbara A.
Grb 7是一种多结构域细胞内信号蛋白，其将活化的酪氨酸激酶与下游信号靶标连接。Grb 7以其在细胞迁移和肿瘤转移中的调节作用而闻名，它还通过将NF-κ B诱导激酶与erbB/EGFR家族受体偶联来调节炎症。Grb 7在这些过程中的“适配器”作用取决于通过其C-末端SH 2结构域与膜相关酪氨酸激酶的结合。Grb 7-SH 2结构域与Grb 2的SH 2结构域（MAP激酶途径的组成部分）具有结构和功能相似性。这两个结构域都显示出对环状（β-转角）配体的不寻常的亲和力。Grb 2-SH 2结构域也显示出独特的自缔合行为，形成交织（“交换”）的二聚体。虽然Grb 7及其SH 2结构域都已知二聚化，但这种自缔合的机制和功能意义尚未完全理解。Grb 7-SH 2结构域中的额外残基有效地延长了其“EF环”，并通过C-末端螺旋的交换使该结构域成为交换二聚化的良好候选物。我们提出了交换的Grb 7-SH 2结构域的二聚体形式的存在，并提供了一个结构模型，通过新的应用程序的核磁共振衍生的同源性模型改进的限制。
Grb7 is a multidomain intracellular signaling protein that links activated tyrosine kinases with downstream signaling targets. Best known for its regulatory role in cell migration and tumor metastasis, Grb7 also regulates inflammation by coupling NF-kappaB-inducing kinase with erbB/EGFR family receptors. The "adaptor" role of Grb7 in these processes depends upon binding to membrane-associated tyrosine kinases through its C-terminal SH2 domain. The Grb7-SH2 domain shares structural and functional similarity with the SH2 domain of Grb2, a constituent of the MAP kinase pathway. Both domains show unusual affinity for cyclic (beta-turn) ligands. The Grb2-SH2 domain also shows distinctive self-association behavior, forming intertwined ("swapped") dimers. While Grb7 and its SH2 domain are each known to dimerize, the mechanisms and functional significance of this self-association are incompletely understood. Additional residues in the Grb7-SH2 domain effectively lengthen its "EF loop" and render the domain a good candidate for swapped dimerization, through exchange of a C-terminal helix. We propose the existence of a swapped dimeric form of the Grb7-SH2 domain and offer a structural model derived through novel application of nuclear magnetic resonance-derived restraints for homology model refinement.