Direct contacts between extracellular membrane-proximal domains are required for VEGF receptor activation and cell signaling.
Direct contacts between extracellular membrane-proximal domains are required for VEGF receptor activation and cell signaling.
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VEGF 受体激活和细胞信号传导需要细胞外膜近端结构域之间的直接接触。
DOI：
10.1073/pnas.0914052107
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发表时间：
2010
影响因子：
11.1
通讯作者：
Schlessinger,Joseph
中科院分区：
文献类型：
--
作者：
Yang,Yan;Xie,Peng;Opatowsky,Yarden;Schlessinger,Joseph
干细胞因子（SCF）受体（也称为KIT）与SCF复合物的细胞外区域的结构分析显示，在第四个igg样结构域（D4）的环中有一个序列基元，该序列基元负责形成同型受体接触，并负责配体诱导的KIT激活和细胞信号传导。在血管内皮生长因子受体1 （VEGFR1）、VEGFR2和VEGFR3的最靠近膜的第7个igg样结构域（D7）中发现了相同的基序。在本报告中，我们证明了配体诱导的酪氨酸自磷酸化和通过VEGFR1或VEGFR2在D7中携带关键残基（Arg726或Asp731）突变的细胞信号传导严重受损。我们还描述了VEGFR2的D7的晶体结构，分辨率为2.7 Å。结构表明，D7的同型接触是由一个原聚体的Arg726和另一个原聚体的Asp731之间形成的盐桥和范德华接触介导的。D7二聚体的结构与与SCF配合物的KIT胞外区晶体结构中D4二聚体的结构非常相似。VEGFR D7和KIT D4在结构和功能上的高度相似性进一步证明了III型和V型rtk具有共同的祖先起源。这也揭示了RTK活化的保守机制和病理活化RTK的药物干预的新靶点。
Structural analyses of the extracellular region of stem cell factor (SCF) receptor (also designated KIT) in complex with SCF revealed a sequence motif in a loop in the fourth Ig-like domain (D4) that is responsible for forming homotypic receptor contacts and for ligand-induced KIT activation and cell signaling. An identical motif was identified in the most membrane-proximal seventh Ig-like domain (D7) of vascular endothelial growth factor receptor 1 (VEGFR1), VEGFR2, and VEGFR3. In this report we demonstrate that ligand-induced tyrosine autophosphorylation and cell signaling via VEGFR1 or VEGFR2 harboring mutations in critical residues (Arg726 or Asp731) in D7 are strongly impaired. We also describe the crystal structure of D7 of VEGFR2 to a resolution of 2.7 Å. The structure shows that homotypic D7 contacts are mediated by salt bridges and van der Waals contacts formed between Arg726 of one protomer and Asp731 of the other protomer. The structure of D7 dimer is very similar to the structure of D4 dimers seen in the crystal structure of KIT extracellular region in complex with SCF. The high similarity between VEGFR D7 and KIT D4 in both structure and function provides further evidence for common ancestral origins of type III and type V RTKs. It also reveals a conserved mechanism for RTK activation and a novel target for pharmacological intervention of pathologically activated RTKs.