Thermodynamic and structural description of allosterically regulated VEGFR-2 dimerization
Thermodynamic and structural description of allosterically regulated VEGFR-2 dimerization
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DOI：
10.1182/blood-2011-11-390922
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发表时间：
2012-02-16
期刊：
影响因子：
20.3
通讯作者：
Ballmer-Hofer, Kurt
中科院分区：
文献类型：
--
作者：
Brozzo, Maurice S.;Bjelic, Sasa;Ballmer-Hofer, Kurt
vegf激活3受体酪氨酸激酶，VEGFR-1、VEGFR-2和VEGFR-3，促进血管生成和淋巴管生成信号。细胞外受体结构域（ECD）由7个igg同源结构域组成；结构域2和3 （D23）代表配体结合结构域，而D4-7的功能尚不清楚。配体结合促进受体二聚化，激发跨膜信号和受体激酶活化。在本研究中，等温滴定量热法表明，VEGF-A、VEGF-C或VEGF-E与D23结合的吉布斯自由能或VEGFR-2的全长ECD以有利熵贡献和焓罚为主。VEGF与ECD结合的自由能比与D23结合的自由能低1.0 ~ 1.7 kcal/mol。基于小角散射数据的VEGF-E/VEGFR-2 ECD复合物模型为D4-7的同型相互作用提供了证据。我们还解决了VEGF-A或VEGF-E与D23之间的配合物的晶体结构，揭示了相似的结合表面和配体与受体之间相似的相互作用，但显示了D23扭曲角的变化。D4-7中能量不利的同型相互作用可能需要受体单体的重新定向，这一机制可能阻止VEGFR-2的配体非依赖性激活，以避免因受体不适当激活而对血液和淋巴管稳态产生的有害后果。(Blood.2012; 119 (7): 1781 - 1788)
VEGFs activate 3 receptor tyrosine kinases, VEGFR-1, VEGFR-2, and VEGFR-3, promoting angiogenic and lymphangiogenic signaling. The extracellular receptor domain (ECD) consists of 7 Ig-homology domains; domains 2 and 3 (D23) represent the ligand-binding domain, whereas the function of D4-7 is unclear. Ligand binding promotes receptor dimerization and instigates transmembrane signaling and receptor kinase activation. In the present study, isothermal titration calorimetry showed that the Gibbs free energy of VEGF-A, VEGF-C, or VEGF-E binding to D23 or the full-length ECD of VEGFR-2 is dominated by favorable entropic contribution with enthalpic penalty. The free energy of VEGF binding to the ECD is 1.0-1.7 kcal/mol less favorable than for binding to D23. A model of the VEGF-E/VEGFR-2 ECD complex derived from small-angle scattering data provided evidence for homotypic interactions in D4-7. We also solved the crystal structures of complexes between VEGF-A or VEGF-E with D23, which revealed comparable binding surfaces and similar interactions between the ligands and the receptor, but showed variation in D23 twist angles. The energetically unfavorable homotypic interactions in D4-7 may be required for re-orientation of receptor monomers, and this mechanism might prevent ligand-independent activation of VEGFR-2 to evade the deleterious consequences for blood and lymph vessel homeostasis arising from inappropriate receptor activation. (Blood.2012;119(7):1781-1788)