Structure and vascular function of MEKK3-cerebral cavernous malformations 2 complex.
Structure and vascular function of MEKK3-cerebral cavernous malformations 2 complex.
复制标题
MEKK3-脑海绵状血管瘤2复合体的结构和血管功能。
DOI：
10.1038/ncomms8937
复制
发表时间：
2015-08-03
影响因子：
16.6
通讯作者：
Su B
中科院分区：
文献类型：
--
作者：
Fisher OS;Deng H;Liu D;Zhang Y;Wei R;Deng Y;Zhang F;Louvi A;Turk BE;Boggon TJ;Su B
脑海绵状血管畸形2（CCM 2）缺失与家族性CCM疾病相关。蛋白激酶MEKK 3（MAP 3 K3）是小鼠胚胎血管生成所必需的，并与CCM 2发生物理相互作用，但这种相互作用是如何介导的及其与脑血管系统的相关性尚不清楚。在这里，我们报告说，Mekk 3在胚胎血管发育中起着内在的作用。诱导性内皮Mekk 3基因敲除可导致新生小鼠多发性颅内出血和脑血管渗漏。我们发现CCM 2的harmonin同源结构域（HHD）和MEKK 3的N端之间的直接相互作用，并确定了2.35 π共晶结构。我们发现Mekk 3缺陷损害神经血管完整性，这部分依赖于Rho-ROCK信号传导，并且MEKK 3：CCM 2相互作用的破坏导致类似的神经血管渗漏。我们的结论是，CCM 2：MEKK 3介导的调节Rho信号是必要的，以维持神经血管的完整性，解开CCM 2损失导致疾病的机制。 蛋白激酶MEKK 3与CCM 2相互作用，CCM 2与主要的脑血管CCM疾病相关。在这里，作者使用结构，生物化学，细胞生物学和体内技术来表明，通过CCM 2：MEKK 3复合物调节Rho信号传导是维持神经血管完整性所必需的。
Cerebral cavernous malformations 2 (CCM2) loss is associated with the familial form of CCM disease. The protein kinase MEKK3 (MAP3K3) is essential for embryonic angiogenesis in mice and interacts physically with CCM2, but how this interaction is mediated and its relevance to cerebral vasculature are unknown. Here we report that Mekk3 plays an intrinsic role in embryonic vascular development. Inducible endothelial Mekk3 knockout in neonatal mice is lethal due to multiple intracranial haemorrhages and brain blood vessels leakage. We discover direct interaction between CCM2 harmonin homology domain (HHD) and the N terminus of MEKK3, and determine a 2.35 Å cocrystal structure. We find Mekk3 deficiency impairs neurovascular integrity, which is partially dependent on Rho–ROCK signalling, and that disruption of MEKK3:CCM2 interaction leads to similar neurovascular leakage. We conclude that CCM2:MEKK3-mediated regulation of Rho signalling is required for maintenance of neurovascular integrity, unravelling a mechanism by which CCM2 loss leads to disease. The protein kinase MEKK3 interacts with CCM2, which is associated with the predominantly cerebrovascular CCM disease. Here the authors use structural, biochemical, cell biology and in vivo techniques to show that regulation of Rho signalling by the CCM2:MEKK3 complex is needed to maintain neurovascular integrity.